TW202233667A - 黏蛋白1結合多肽、多核苷酸、載體、細胞、嵌合抗原受體、免疫細胞以及組成物 - Google Patents
黏蛋白1結合多肽、多核苷酸、載體、細胞、嵌合抗原受體、免疫細胞以及組成物 Download PDFInfo
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Abstract
提供一種與黏蛋白1結合的多肽、一種對所述多肽進行編碼的分離的多核苷酸、一種包含所述多核苷酸的載體以及一種包含所述載體的細胞。亦提供一種包含與黏蛋白1結合的多肽的嵌合抗原受體、一種對所述嵌合抗原受體進行編碼的分離的多核苷酸、一種包含所述多核苷酸的載體、一種對所述嵌合抗原受體進行表達的免疫細胞、以及各自包含前述者的一種用於治療癌症的組成物及一種治療癌症的方法。
Description
[相關申請案的交叉參考]
本申請案基於分別於2020年12月24日及2021年10月15日提出申請的韓國專利申請案第10-2020-0183768號及韓國專利申請案第10-2021-0137757號並主張其等的優先權,所述韓國專利申請案的揭露內容全部特此併入本案供參考。
[技術領域]
提供一種與黏蛋白1結合的多肽、一種對所述多肽進行編碼的分離的多核苷酸、一種包含所述多核苷酸的載體以及一種包含所述載體的細胞。此外,提供一種包含與黏蛋白1結合的多肽的嵌合抗原受體、一種對所述嵌合抗原受體進行編碼的分離的多核苷酸、一種包含所述多核苷酸的載體、一種對所述嵌合抗原受體進行表達的免疫細胞、以及各自包含前述者的一種用於治療癌症的組成物及一種治療癌症的方法。
黏蛋白1是一種膜結合型糖蛋白,存在於體內幾乎所有器官的上皮細胞中。黏蛋白1是一種由N-末端亞單位(MUC1-N)與C-末端亞單位(MUC1-C)的非共價相互作用形成的異二聚體蛋白(heterodimeric protein)。MUC1-C形成細胞外域、跨膜域及細胞質尾。MUC1-N重複地包括含有20個胺基酸的縱排重複(tandem repeat,TR)(HGVTSAPDTRPAPGSTAPPA)、包括糖基化位點,且與MUC1-C的細胞外域相互作用並繼續與MUC1-C連接。
在正常上皮細胞中,黏蛋白1以低水準表達,且其表達僅限於上皮細胞的頂膜。然而,已知黏蛋白1在實體癌(例如乳腺癌、肺癌、結腸直腸癌、皮膚癌、甲狀腺癌、胃癌、胰腺癌、腎癌、卵巢癌、宮頸癌等)中過表達(overexpress),且已知在整個細胞表面上隨機表達並異常糖基化。因此,已知黏蛋白1可用作對癌症病變進行檢測的靶分子或用作用於治療癌症的靶分子。
[技術問題]
目前,有許多關於抗MUC1抗體用於癌症治療的報道。然而,使用抗體的抗癌療法僅適用於具有被抗體特異性識別的抗原的癌細胞,效果持續時間短,且在其長期使用期間經常出現耐藥性。藉此,需要開發一種能夠藉由激活體內免疫系統對各種癌症持續發揮強抗癌效果的技術。
[技術解決方案]
提供一種與黏蛋白1結合的多肽。
實施例提供一種對黏蛋白1結合多肽進行編碼的分離的多核苷酸。
其他實施例提供一種包含對黏蛋白1結合多肽進行編碼的多核苷酸的載體。
其他實施例提供一種包含載體的細胞,所述載體包含對黏蛋白1結合多肽進行編碼的多核苷酸。
其他實施例提供一種包含黏蛋白1結合多肽的嵌合抗原受體。
其他實施例提供一種對嵌合抗原受體進行編碼的分離的多核苷酸。
其他實施例提供一種包含對嵌合抗原受體進行編碼的多核苷酸的載體。
其他實施例提供一種免疫細胞,所述免疫細胞對嵌合抗原受體進行表達或者包含對嵌合抗原受體進行編碼的多核苷酸。
其他實施例提供一種用於治療癌症的組成物,所述組成物包含:黏蛋白1結合多肽;分離的多核苷酸,對黏蛋白1結合多肽進行編碼;載體,包含對黏蛋白1結合多肽進行編碼的多核苷酸;細胞,包含對黏蛋白1結合多肽進行編碼的多核苷酸;嵌合抗原受體,包含黏蛋白1結合多肽;分離的多核苷酸,對嵌合抗原受體進行編碼;載體,包含對嵌合抗原受體進行編碼的多核苷酸;或者免疫細胞,包含對嵌合抗原受體進行編碼的所述多核苷酸或者對嵌合抗原受體進行表達。
根據本發明的一態樣,提供一種與黏蛋白1結合的多肽。在一較佳實施例中,本揭露的與黏蛋白1結合的多肽可為抗體或其抗原結合片段。
在一實施例中,提供一種與黏蛋白1結合的多肽,所述多肽包含選自以下重鏈可變(heavy chain variable,VH)區及輕鏈可變(light chain variable,VL)區的一對VH區及VL區:
-包含分別由胺基酸序列SEQ ID NO: 1、SEQ ID NO: 2及SEQ ID NO: 3表示的互補決定區(complementarity-determining region,CDR)1、CDR 2及CDR 3的VH區、及包含分別由胺基酸序列SEQ ID NO: 4、SEQ ID NO: 5及SEQ ID NO: 6表示的CDR 1、CDR 2及CDR 3的VL區;
-包含分別由胺基酸序列SEQ ID NO: 11、SEQ ID NO: 12及SEQ ID NO: 13表示的CDR 1、CDR 2及CDR 3的VH區、及包含分別由胺基酸序列SEQ ID NO: 14、SEQ ID NO: 15及SEQ ID NO: 16表示的CDR 1、CDR 2及CDR 3的VL區;
-包含分別由胺基酸序列SEQ ID NO: 21、SEQ ID NO: 22及SEQ ID NO: 23表示的CDR 1、CDR 2及CDR 3的VH區、及包含分別由胺基酸序列SEQ ID NO: 24、SEQ ID NO: 25及SEQ ID NO: 26表示的CDR 1、CDR 2及CDR 3的VL區;
-包含分別由胺基酸序列SEQ ID NO: 31、SEQ ID NO: 32及SEQ ID NO: 33表示的CDR 1、CDR 2及CDR 3的VH區及包含分別由胺基酸序列SEQ ID NO: 44、SEQ ID NO: 45及SEQ ID NO: 46表示的CDR 1、CDR 2及CDR 3的VL區;
-包含分別由胺基酸序列SEQ ID NO: 51、SEQ ID NO: 52及SEQ ID NO: 53表示的CDR 1、CDR 2及CDR 3的VH區、及包含分別由胺基酸序列SEQ ID NO: 54、SEQ ID NO: 55及SEQ ID NO: 56表示的CDR 1、CDR 2及CDR 3的VL區;
-包含分別由胺基酸序列SEQ ID NO: 61、SEQ ID NO: 62及SEQ ID NO: 63表示的CDR 1、CDR 2及CDR 3的VH區、及包含分別由胺基酸序列SEQ ID NO: 64、SEQ ID NO: 65及SEQ ID NO: 66表示的CDR 1、CDR 2及CDR 3的VL區;
-包含分別由胺基酸序列SEQ ID NO: 71、SEQ ID NO: 72及SEQ ID NO: 73表示的CDR 1、CDR 2及CDR 3的VH區、及包含分別由胺基酸序列SEQ ID NO: 74、SEQ ID NO: 75及SEQ ID NO: 76表示的CDR 1、CDR 2及CDR 3的VL區;
-包含分別由胺基酸序列SEQ ID NO: 81、SEQ ID NO: 82及SEQ ID NO: 83表示的CDR 1、CDR 2及CDR 3的VH區、及包含分別由胺基酸序列SEQ ID NO: 84、SEQ ID NO: 85及SEQ ID NO: 86表示的CDR 1、CDR 2及CDR 3的VL區;以及
-包含分別由胺基酸序列SEQ ID NO: 91、SEQ ID NO: 92及SEQ ID NO: 93表示的CDR 1、CDR 2及CDR 3的VH區、及包含分別由胺基酸序列SEQ ID NO: 94、SEQ ID NO: 95及SEQ ID NO: 96表示的CDR 1、CDR 2及CDR 3的VL區。
[表1]
克隆 名稱 | CDR | |||||
VH | VL | |||||
CDR1 | CDR2 | CDR3 | CDR1 | CDR2 | CDR3 | |
2445_1F09 | GFTVSSNY (SEQ ID NO: 1) | IYSGGST (SEQ ID NO: 2) | DRGWNHGMDV (SEQ ID NO: 3) | SSEVGSRY (SEQ ID NO: 4) | KND (SEQ ID NO: 5) | AAWDDSLNGYV (SEQ ID NO: 6) |
2447_2H08 | GYTFTNYG (SEQ ID NO: 11) | ISAYNGNT (SEQ ID NO: 12) | DPHILTGYYRGGWFDP (SEQ ID NO: 13) | SLRTSY (SEQ ID NO: 14) | GKT (SEQ ID NO: 15) | HSRDSNDNYLEVV (SEQ ID NO: 16) |
2447_3A01 | GFTFDDYA (SEQ ID NO: 21) | ISWNSGSI (SEQ ID NO: 22) | DISSGWYPGTFDY (SEQ ID NO: 23) | SLRSYY (SEQ ID NO: 24) | GKN (SEQ ID NO: 25) | SSRDSSDDVV (SEQ ID NO: 26) |
2447_3A08 | GYTFTSYG (SEQ ID NO: 31) | ISAYNGNT (SEQ ID NO: 32) | DRATIFGVVTPFDY (SEQ ID NO: 33) | SIRSYS (SEQ ID NO: 34) | GKN (SEQ ID NO: 35) | NSRDSSGNRVV (SEQ ID NO: 36) |
2447_3A09 | GFTFDDYA (SEQ ID NO: 41) | ISWNSGSI (SEQ ID NO: 42) | DVSSGWYWYAFDI (SEQ ID NO: 43) | SLRSYY (SEQ ID NO: 44) | GKN (SEQ ID NO: 45) | NSRDSGGSVV (SEQ ID NO: 46) |
2447_3A12 | GYTFTSYG (SEQ ID NO: 51) | ISAYNGNT (SEQ ID NO: 52) | DPHILTGYYRGGWFDP (SEQ ID NO: 53) | SLRSYY (SEQ ID NO: 54) | GKN (SEQ ID NO: 55) | NSRDSSGNHRV (SEQ ID NO: 56) |
2447_3B07 | GFTFDDYA (SEQ ID NO: 61) | TSWDGGST (SEQ ID NO: 62) | DHSSGWYNGGMDV (SEQ ID NO: 63) | SLRSYY (SEQ ID NO: 64) | GKN (SEQ ID NO: 65) | NSRDSSGNHVV (SEQ ID NO: 66) |
2447_3C08 | GFTFDDYA (SEQ ID NO: 71) | ISWNSGSI (SEQ ID NO: 72) | DRGSGYEGNYYGMDV (SEQ ID NO: 73) | SLRSYY (SEQ ID NO: 74) | GKN (SEQ ID NO: 75) | NSRDSSGNHYV (SEQ ID NO: 76) |
2447_3H02 | GFTFDDYA (SEQ ID NO: 81) | ISWDSGSI (SEQ ID NO: 82) | DVSSGWYWYAFDI (SEQ ID NO: 83) | ILRSYY (SEQ ID NO: 84) | GKN (SEQ ID NO: 85) | NSRDSSGNRVV (SEQ ID NO: 86) |
2447_3H08 | GFTFDDYA (SEQ ID NO: 91) | ISWNSGSI (SEQ ID NO: 92) | DRSSGWYTGSFDY (SEQ ID NO: 93) | SLRSYY (SEQ ID NO: 94) | GKN (SEQ ID NO: 95) | QSRDSSDNRVL (SEQ ID NO: 96) |
在另一實施例中,提供一種與黏蛋白1結合的多肽,所述多肽包含選自以下重鏈可變(VH)區及輕鏈可變(VL)區的一對VH區及VL區:
-包含胺基酸序列SEQ ID NO: 7的VH區及包含胺基酸序列SEQ ID NO: 8的VL區;
-包含胺基酸序列SEQ ID NO: 17的VH區及包含胺基酸序列SEQ ID NO: 18的VL區;
-包含胺基酸序列SEQ ID NO: 27的VH區及包含胺基酸序列SEQ ID NO: 28的VL區;
-包含胺基酸序列SEQ ID NO: 37的VH區及包含胺基酸序列SEQ ID NO: 38的VL區;
-包含胺基酸序列SEQ ID NO: 47的VH區及包含胺基酸序列SEQ ID NO: 48的VL區;
-包含胺基酸序列SEQ ID NO: 57的VH區及包含胺基酸序列SEQ ID NO: 58的VL區;
-包含胺基酸序列SEQ ID NO: 67的VH區及包含胺基酸序列SEQ ID NO: 68的VL區;
-包含胺基酸序列SEQ ID NO: 77的VH區及包含胺基酸序列SEQ ID NO: 78的VL區;
-包含胺基酸序列SEQ ID NO: 87的VH區及包含胺基酸序列SEQ ID NO: 88的VL區;以及
-包含胺基酸序列SEQ ID NO: 97的VH區及包含胺基酸序列SEQ ID NO: 98的VL區。
[表2]
克隆 名稱 | VH | VL |
2445_1F09 | EVQLLETGGGLIQPGGSLRLSCAASGFTVSSNYMSWVRQAPGKGLEWVSVIYSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRGWNHGMDVWGQGTLVTVSS (SEQ ID NO: 7) | QSGLTQPPSASGTPGQRVTISCSGGSSEVGSRYVSWYQQLPGTAPRLLIYKNDRRPSGVPDRFSGSKSGSSASLAISGLRSEDEADYYCAAWDDSLNGYVFGTGTKLTVL (SEQ ID NO: 8) |
2447_2H08 | EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDPHILTGYYRGGWFDPWGQGTTVTVSS (SEQ ID NO: 17) | SYELTQDPAVSVALGQTVTITCQGDSLRTSYAGWLQQKPGQAPVLVLYGKTSRPSGIPDRFSGSTSGNTASLTITGAQAEDEAEYFCHSRDSNDNYLEVVFGGGTKLTVL (SEQ ID NO: 18) |
2447_3A01 | EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIVYADFVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDISSGWYPGTFDYWGQGTLVTVSS (SEQ ID NO: 27) | SYELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTVTGAQAEDEADYYCSSRDSSDDVVFGGGTQLTVL (SEQ ID NO: 28) |
2447_3A08 | EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDRATIFGVVTPFDYWGQGTLVTVSS (SEQ ID NO: 37) | SYELTQDPAVSVALGQTVRITCQGDSIRSYSASWYQQKPGQAPRLVIYGKNNRPSGIPDRVSGSTSGNTASLTVTGAQAEDEADYYCNSRDSSGNRVVFGGGTQLTVL (SEQ ID NO: 38) |
2447_3A09 | EVQLLESGGGLVQPGRSLRLSCAATGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTASYYCAKDVSSGWYWYAFDIWGQGTLVTVSS (SEQ ID NO: 47) | SYELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPGRFSGSSSGNTASLTVTGAQAEDEADYYCNSRDSGGSVVFGGGTKLTVL (SEQ ID NO: 48) |
2447_3A12 | EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLRGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDPHILTGYYRGGWFDPWGQGTLVTVSS (SEQ ID NO: 57) | SYELTQDPAVSVVLGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDSSGNHRVFGGGTKLTVL (SEQ ID NO: 58) |
2447_3B07 | QVQLVESGGVVVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGRGLEWVSLTSWDGGSTYYADSVKGRFTISRDNSKNSLYLQMNSLRAEDTALYYCAKDHSSGWYNGGMDVWGQGTMVTVSS (SEQ ID NO: 67) | SYELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDSSGNHVVFGGGTKLTVL (SEQ ID NO: 68) |
2447_3C08 | EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDRGSGYEGNYYGMDVWGQGTLVTVSS (SEQ ID NO: 77) | SYELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGTTSGNTASLTITGAQAEDEADYYCNSRDSSGNHYVFGTGTKVTVL (SEQ ID NO: 78) |
2447_3H02 | EVQLLESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWDSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDVSSGWYWYAFDIWGQGTLVTVSS (SEQ ID NO: 87) | SYELTQDPAVSVALGQTVRITCQGDILRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDSSGNRVVFGGGTKLTVL (SEQ ID NO: 88) |
2447_3H08 | EVQLLESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRSSGWYTGSFDYWGQGTLVTVSS (SEQ ID NO: 97) | SYELTQDPAVSVALGQTVRITCQGDSLRSYYASWYRQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTIIGAQAEDEADYYCQSRDSSDNRVLFGGGTKVTVL (SEQ ID NO: 98) |
如本文中所用,用語「抗體」泛指與特定抗原進行特異性結合的蛋白質,且以最廣泛的意義使用,且其可為藉由抗原刺激在免疫系統中產生的蛋白質、或化學合成的蛋白質、或重組製備的蛋白質。其類型沒有特別限制。具體而言,抗體囊括單株抗體(包括全長單株抗體)、多株抗體、多特異性抗體(例如,雙特異性抗體)、合成抗體(亦稱為抗體模擬物(antibody mimetics))、嵌合抗體、人源化抗體、人抗體或抗體融合蛋白(亦稱為抗體綴合物(antibody conjugate)),提供的此種抗體表現出所需的生物活性。
完整的抗體(例如IgG型)具有含有兩個全長輕鏈及兩個全長重鏈的結構,每一輕鏈藉由二硫鍵與重鏈相關聯。抗體的恆定區分為重鏈恆定區與輕鏈恆定區,其中重鏈恆定區具有伽馬(γ)類型、謬(μ)類型、阿爾法(α)類型、德爾塔(δ)類型或伊普西隆(ε)類型以及伽馬1(γ1)、伽馬2(γ2)、伽馬3(γ3)、伽馬4(γ4)、阿爾法1(α1)或阿爾法2(α2)的子類,而輕鏈恆定區具有卡帕(κ)類型或蘭姆達(λ)類型。
用語「抗原結合片段」是指抗體的片段,其即使至少部分胺基酸在全長鏈中存在缺失亦能夠與抗原特異性結合。此種片段具有生物活性,乃因它與靶抗原結合並與包括完整抗體的其它抗原結合分子競爭結合至給定的表位。抗原結合片段可不包括完整抗體的可結晶片段(fragment crystallizable,Fc)區的恆定重鏈域(即,根據抗體同種型的CH2、CH3及CH4)。抗原結合片段的實例可包括單鏈可變片段(single chain variable fragment,scFv)(例如scFv、(scFv)
2等)、片段抗原結合(fragment antigen binding,Fab)(例如Fab、Fab’、F(ab’)
2等)、域抗體、肽抗體、微抗體、內抗體、雙抗體、三抗體、四抗體或單鏈抗體等,但不限於此。此外,抗原結合片段可為scFv或其中scFv與免疫球蛋白(例如,IgA、IgD、IgE、IgG(IgG1、IgG2、IgG3、IgG4)、IgM等)的Fc區融合的融合多肽(scFv-Fc)、或者其中scFv與輕鏈恆定區(例如κ或λ)融合的融合多肽(scFv-Ck(κ恆定區)或scFv-Cλ(λ恆定區)),但不限於此。
用語「重鏈」被解釋為具有包括全長重鏈及其片段的含義,所述全長重鏈包括可變區域V
H、及三個恆定區域C
H1、C
H2及C
H3以及鉸鏈,所述可變區域V
H包括具有足以對抗原賦予特異性的可變區序列的胺基酸序列。此外,用語「輕鏈」被解釋為具有包括全長輕鏈及其片段的含義,所述全長輕鏈包括可變區域V
L及恆定區域C
L,所述可變區域V
L包括具有足以對抗原賦予特異性的可變區序列的胺基酸序列。
用語「互補決定區(CDR)」是指抗體可變區中的區,其對抗原賦予結合特異性或結合親和力。一般而言,在重鏈可變區中存在三個CDR(CDR-H1、CDR-H2、CDR-H3),且在輕鏈可變區中存在三個CDR(CDR-L1、CDR-L2、CDR-L3)。CDR可為與抗原或表位結合的抗體或其片段提供關鍵的接觸殘基。用語「框架區(framework region,FR)」是指重鏈可變區及輕鏈可變區的非CDR區。一般而言,在重鏈可變區中存在四個FR(FR-H1、FR-H2、FR-H3及FR-H4),且在輕鏈可變區中存在四個FR(FR-L1、FR-L2、FR-L3及FR-L4)。給定CDR或FR的精確胺基酸序列邊界可使用許多熟知的方案(例如卡巴特編號方案(Kabat numbering scheme)、喬蒂亞編號方案(Chothia numbering scheme)、接觸編號方案、免疫遺傳學(immunogenetic,IMGT)編號方案、阿霍編號方案(Aho numbering scheme)、阿布編號方案(AbM numbering scheme)等)中的任一種來容易地確定。
用語「可變區」是指抗體的重鏈或輕鏈的參與抗體與抗原的結合的域。重鏈可變(VH)區及輕鏈可變(VL)區一般而言具有相似的結構,且每一域包括四個保守的框架區(FR)及三個CDR。
在具體實施例中,本揭露的黏蛋白1結合多肽可為單鏈可變片段(scFv)、肽抗體、抗原結合片段(Fab)、單株抗體、雙特異性抗體、微抗體、域抗體、合成抗體、嵌合抗體、人源化抗體、人抗體或抗體融合蛋白,但不限於此。
在較佳的具體實施例中,本揭露的黏蛋白1結合多肽可為單鏈可變片段(scFv)。
用語「單鏈可變片段(scFv)」是指其中抗體的重鏈可變(VH)區與輕鏈可變(VL)區藉由共價鍵連接的單鏈抗體片段。VH區與VL區可直接或藉由連接子彼此連接。
連接子可為水溶性連接子及/或可撓性連接子。舉例而言,VH的N-末端與VL的C-末端或者VH的C-末端與VL的N-末端可藉由連接子彼此連接。連接子可為肽連接子,所述肽連接子例如具有10至30個胺基酸、10至25個胺基酸、10至20個胺基酸、10至15個胺基酸、15至30個胺基酸、15至25個胺基酸、15至20個胺基酸的長度,具體而言具有10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個胺基酸,但不限於此。
適用於連接子的胺基酸序列是本領域中已知的。舉例而言,連接子可富含甘胺酸以獲得靈活性,且可包括絲胺酸(Ser)、天冬醯胺(Asn)、丙胺酸(Ala)或蘇胺酸(Thr)以獲得溶解性。連接子可由總共1至100、2至50或5至25個選自由Gly、Asn、Ser、Thr及Ala組成的群組中的一或多個組成。對於非限制性實例,連接子的胺基酸序列可為具有不同數目的GGGS或GGGGS重複(例如,GGGS或GGGGS的2、3、4及5個重複)的序列。舉例而言,連接子可為GGGGSGGGGSGGGGS、GGGGSGGGGSGGGGSGGGGS或GGGGSGGGGSGGGAS,但不限於此。
儘管移除恆定區並引入連接子,scFv仍保留原始抗體的抗原特異性。scFv可由對VH區及VL區進行編碼的多核苷酸表達,但不限於此。
在較佳的實施例中,提供一種scFv多肽,所述scFv多肽包含選自由以下組成的群組中的胺基酸序列:SEQ ID NO: 9、SEQ ID NO: 19、SEQ ID NO: 29、SEQ ID NO: 39、SEQ ID NO: 49、SEQ ID NO: 59、SEQ ID NO: 69、SEQ ID NO: 79、SEQ ID NO: 89及SEQ ID NO: 99。
在本揭露中,保留與抗體或抗原結合片段的活性等同的活性的變體,舉例而言,與本文中所述的胺基酸序列具有約80%、約81%、約82%、約83%、約84%、約85%、約86%、約87%、約88%、約89%、約90%、約91%、約92%、約93%、約94%、約95%、約96%、約97%、約98%或約99%或大於99%的同一性並保留與其等同的生物活性的變體可亦包含於本揭露的範圍內。
根據本發明的另一態樣,提供一種對黏蛋白1結合多肽進行編碼的分離的多核苷酸。
在一較佳的實施例中,所述多核苷酸可包括選自由以下組成的群組中的核苷酸序列:SEQ ID NO: 10、SEQ ID NO: 20、SEQ ID NO: 30、SEQ ID NO: 40、SEQ ID NO: 50、SEQ ID NO: 60、SEQ ID NO: 70、SEQ ID NO: 80、SEQ ID NO: 90及SEQ ID NO: 100。此外,本發明可包括一種分離的多核苷酸,所述分離的多核苷酸對與所述序列具有約90%、約91%、約92%、約93%、約94%、約95%、約96%、約97%、約98%或約99%或大於99%的同一性並保持與其等同的活性的多肽進行編碼。在實施例中,多核苷酸可針對人類中的表達進行密碼子優化。
根據又一態樣,提供一種包含對黏蛋白1結合多肽進行編碼的多核苷酸的載體。
在載體中,多核苷酸可可操作地連接至啟動子。用語「可操作地連接」是指核苷酸表達控制序列(例如啟動子序列)與另一核苷酸序列之間的功能性連接。控制序列可可操作地連接以對另一核苷酸序列的轉錄及/或轉譯進行控制。
載體可被構建為通常用於克隆或表達的載體。用於表達的載體可為本領域中常用的在植物、動物或微生物中表達外源蛋白的載體。可藉由本領域中已知的各種方法構建載體。
可使用原核細胞或真核細胞作為宿主來構建載體。舉例而言,當使用的載體是表達載體且使用原核細胞作為宿主時,載體一般而言可包括:能夠啟動轉錄的強啟動子(例如,pL
λ啟動子、巨細胞病毒(cytomegalovirus,CMV)啟動子、
色胺酸(
trp)啟動子、
乳糖(
lac)啟動子、
tac啟動子、T7啟動子等);用於進行起始轉譯的核糖體結合位點;以及轉錄/轉譯終止序列。當使用真核細胞作為宿主時,包含於載體中並在真核細胞中起作用的複製起點可包括f1複製起點、SV40複製起點、pMB1複製起點、腺病毒複製起點、腺相關病毒(adeno-associated virus,AAV)複製起點、血源性病毒(Blood-borne Virus,BBV)複製起點等,但不限於此。此外,可使用來源於哺乳動物細胞基因組的啟動子(例如金屬硫蛋白啟動子)或來源於哺乳動物病毒的啟動子(例如腺病毒晚期啟動子、痘瘡病毒7.5K啟動子、SV40啟動子、巨細胞病毒啟動子及單純皰疹病毒(herpes simplex virus,HSV)的
tk啟動子),且轉錄終止序列一般可為多腺苷酸化序列。視需要,載體可更包括增強子序列、5’-非轉譯區及3’-非轉譯區、分泌訊號序列、剪接點、選擇標記(例如抗生素抗性基因)等。
根據又一態樣,提供一種包含載體的細胞,所述載體包含對黏蛋白1結合多肽進行編碼的多核苷酸。
可藉由將載體引入至合適的宿主細胞來獲得細胞。包含載體的宿主細胞可用於對載體中所包含的多核苷酸進行克隆或表達。宿主細胞是能夠穩定且連續地對載體進行克隆或表達的細胞,且可使用本領域中已知的任何宿主細胞。舉例而言,原核細胞可包括例如大腸桿菌(
E. coli)JM109、大腸桿菌BL21、大腸桿菌RR1、大腸桿菌LE392、大腸桿菌B、大腸桿菌X 1776、大腸桿菌W3110、芽孢桿菌屬菌株(例如
枯草桿菌、
蘇力菌)、以及
腸桿菌科菌株(例如
鼠傷寒沙門氏菌、
黏質沙雷氏菌及各種
假單胞菌種)。當轉化至真核細胞中時,宿主細胞可包括酵母(
釀酒酵母)細胞、昆蟲細胞、植物細胞及動物細胞(例如,Sp2/0、中國倉鼠卵巢(Chinese hamster ovary,CHO)K1、CHO DG44、PER.C6、W138、幼倉鼠腎(baby hamster kidney,BHK)、COS-7、293、HepG2、Huh7、3T3、RIN、馬丁達比狗腎(Madin-Darby canine kidney,MDCK)細胞系等),但不限於此。
多核苷酸或包含多核苷酸的載體向宿主細胞中的遞送(引入)可藉由使用本領域中廣泛已知的遞送方法來實行。關於遞送方法,例如當宿主細胞是原核細胞時,可使用CaCl
2方法或電穿孔法,且當宿主細胞是真核細胞時,可使用顯微注射法、磷酸鈣沈澱法、電穿孔法、脂質體介導的轉染法及基因轟擊,但不限於此。
根據本領域中眾所習知的方法,可使用由選擇標記表達的表型容易地實行對轉化的宿主細胞進行選擇的方法。舉例而言,當選擇標記是特定的抗生素抗性基因時,可藉由在含有抗生素的培養基中對轉化體進行培養來容易地選擇轉化體。可將轉化的宿主細胞培養達足以表達或分泌多肽的時段,且可藉由常用的對蛋白質進行分離及純化的方法對多肽進行分離及純化,例如使用溶解性的方法(例如鹽析、溶劑沈澱等)、使用分子量差異的方法(例如透析、超濾、凝膠過濾、十二烷基硫酸鈉-聚丙烯醯胺凝膠電泳等)、使用電荷的方法(例如離子交換層析法或羥基磷灰石層析法等)、使用特定親和力的方法(例如親和力層析法等)、利用疏水性差異的方法(例如反相高效液相層析法等)、使用等電點差的方法(例如等電點電泳法等)。
根據本發明的又一態樣,提供一種包含黏蛋白1結合多肽的嵌合抗原受體(CAR)。黏蛋白1結合多肽適用於在嵌合抗原受體中使用,乃因它可被改造成作為單鏈的一部分與其他CAR成分一起表達。
嵌合抗原受體通常可包括:包含黏蛋白1結合多肽的細胞外域;跨膜域;細胞內傳訊域或T細胞活化域。此外,細胞外域可更包括多肽與跨膜域之間的間隔區(或鉸鏈區)。此外,嵌合抗原受體可更包括一或多個共刺激域,且較佳為共刺激域可位於跨膜域與細胞內傳訊域之間。
藉此,在一較佳的實施例中,嵌合抗原受體可包括:包含黏蛋白1結合多肽的細胞外域;鉸鏈域;跨膜域;一或多個共刺激域;以及細胞內傳訊域。每一域可為異質的。換言之,可由來源於不同蛋白質鏈的序列組成。每一域可藉由短寡肽連接子或多肽連接子(例如具有2至10個胺基酸長度的連接子)進行連接。另外,嵌合抗原受體可由其中各個域連接的一條多肽鏈組成。
細胞外域包括如上所述的黏蛋白1結合多肽,其識別在癌細胞表面上進行表達的黏蛋白1。
細胞外域可更包括間隔區(或鉸鏈區)。間隔區可位於黏蛋白1結合多肽與跨膜域之間。間隔區使得黏蛋白1結合多肽能夠在距CAR-T細胞的細胞膜預定距離處更靈活地識別靶抗原。間隔區通常可為具有10或大於10個胺基酸的長度(例如,具有10至300個胺基酸的長度、具有10至250個胺基酸的長度、具有10至200個胺基酸的長度、具有10至150個胺基酸的長度、具有10至100個胺基酸的長度、具有10至50個胺基酸的長度)的多肽,但不限於此。
間隔區可藉由CD8α或CD28的鉸鏈區、免疫球蛋白(IgG)的恆定區等例示,且藉此可引入突變以移除脫靶效應。舉例而言,免疫球蛋白恆定區可來源於單獨的IgG鉸鏈、CH2域及CH3域(例如Fc區)的一部分或全部。IgG可較佳為IgG2或IgG4。在具體實施例中,間隔區可為包含來源於IgG2、IgG4及/或IgG2及IgG4的鉸鏈、CH2及CH3序列中的一或多者的嵌合多肽。在具體實施例中,鉸鏈域可由序列SEQ ID NO: 112表示,但不限於此。
跨膜域用於連接細胞膜域與細胞膜內部的傳訊域,且可來源於天然源或合成源。當來源於天然源時,跨膜域可來源於任何膜結合蛋白或跨膜蛋白。舉例而言,跨膜域可為T細胞受體α、β或ζ鏈、CD3ε、CD4、CD5、CD8、CD9、CD16、CD22、CD28、CD33、CD37、CD45、CD64、CD80、CD86、CD134、CD137或CD154的跨膜域,但不限於此。在一較佳的實施例中,跨膜域可為CD28或CD8的跨膜域,但不限於此。當來源於合成源時,合成跨膜域可包括疏水性殘基(例如白胺酸及纈胺酸),且可在其每一端包括苯丙胺酸、色胺酸及纈胺酸,但不限於此。在一實施例中,跨膜域可由序列SEQ ID NO: 113表示,但不限於此。
共刺激域是共刺激訊號傳遞至的位點,且是CAR-T細胞傳輸訊號以觸發免疫反應及增殖的位點。可選擇性地引入共刺激域以改善CAR-T細胞增殖、細胞毒性、持續反應及壽命延長。共刺激域可為選自以下傳訊域中的一或多個(例如一個、二個或三個):CD28、OX-40(CD134)、4-1BB(CD137)、CD2、CD7、CD27、CD30、CD40、PD-1、ICOS、LFA-1(CD11a/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7-H3)、LIGHT、(TNFSF14)、NKG2C、Igα(CD79a)、DAP-10、Fcγ受體、主要組織相容性複合體(major histocompatibility complex,MHC)I類分子、腫瘤壞死因子(tumor necrosis factor,TNF)受體蛋白、免疫球蛋白、細胞因子受體、整聯蛋白、傳訊淋巴細胞活化分子(signaling lymphocytic activation molecule,SLAM)、活化自然殺手(natural killer,NK)細胞受體、B及T淋巴細胞衰減因子(B- and T-lymphocyte attenuator,BTLA)、Toll配體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2Rβ、IL-2Rγ、IL-7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD11d、ITGAE、CD103、ITGAL、CD11a、LFA-1、ITGAM、CD11b、ITGAX、CD11c、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRTAM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB-A、Ly108)、SLAMF1(CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、或者CD19a,但不限於此。在一較佳的實施例中,共刺激域可為選自以下傳訊域中的一或多個(例如一個、二個或三個):CD28、OX-40(CD134)、4-1BB(CD137)、CD27或者ICOS,但不限於此。在實施例中,共刺激域可由序列SEQ ID NO: 114表示,但不限於此。
細胞內傳訊域是激活T細胞對結合至黏蛋白1結合多肽的抗原的免疫反應的位點。細胞內傳訊域可為T細胞受體(T cell receptor,TCR)的組成部分,或者可包括被稱為免疫受體酪胺酸系激活基序(immunoreceptor tyrosine-based activation motif,ITAM)的傳訊基序。舉例而言,細胞內傳訊域可為來源於TCR或CD3ζ、FcRγ、CD3γ、CD3δ及CD3ε的傳訊域,但不限於此。對於較佳的實例,細胞內傳訊域可為CD3ζ的傳訊域,但不限於此。當細胞外域的黏蛋白1結合多肽區與靶結合時,細胞內傳訊域可激活CAR-T細胞。舉例而言,CAR可刺激T細胞功能,例如細胞溶解活性或T輔助活性,且可誘導細胞因子或其他因子的分泌。在一些實施例中,細胞內傳訊域可由序列SEQ ID NO: 115表示,但不限於此。
在一些實施例中,CAR可以包括訊號序列的形式來表達。另外,CAR可與可用於進行監測表達的附加序列(例如,核糖體跳躍序列(例如2A肽或截短的細胞表面多肽(tHER2或tEGFR或截短的PSMA等)))一起表達。
根據本發明的又一態樣,提供一種對嵌合抗原受體進行編碼的分離的多核苷酸。在一些實施例中,多核苷酸可針對人類中的表達進行密碼子優化。
根據本發明的又一態樣,提供一種包含對嵌合抗原受體進行編碼的多核苷酸的載體。載體可被構建為用於進行基因克隆的載體、用於蛋白質表達的載體或用於基因遞送的載體。用於進行克隆或表達的載體的細節如上所述。
本領域中已知的任何載體可適用於本發明。舉例而言,載體可為病毒載體。舉例而言,載體是逆轉錄病毒載體、脫氧核糖核酸(deoxyribonucleic acid,DNA)載體、鼠白血病病毒載體、SFG載體、質粒、核糖核酸(ribonucleic acid,RNA)載體、腺病毒載體、桿狀病毒載體、愛潑斯坦-巴爾(Epstein Barr)病毒載體、乳頭瘤病毒載體、痘瘡病毒載體、單純皰疹病毒載體、腺病毒相關載體(AAV)或慢病毒載體,但不限於此。
根據本發明的又一態樣,提供一種對包含黏蛋白1結合多肽的嵌合抗原受體進行表達的免疫細胞。
免疫細胞可包括T細胞、腫瘤浸潤淋巴細胞(tumor infiltrating lymphocyte,TIL)、自然殺手(NK)細胞、TCR表達的細胞、樹突細胞或NK-T細胞,但不限於此。另外,免疫細胞可來源於人類誘導性富潛能幹細胞(induced pluripotent stem cell,iPSC)。免疫細胞可來源於任何已知來源。舉例而言,免疫細胞可在體外(
in vitro)自造血幹細胞群分化出或者自患者獲得。免疫細胞可自例如周邊血單核細胞(peripheral blood mononuclear cell,PBMC)、骨髓、淋巴結組織、臍帶血、胸腺組織、來自感染位點的組織、腹水、胸腔積液、脾組織及腫瘤獲得。另外,免疫細胞可來源於相關領域中可獲得的一或多種免疫細胞系。
免疫細胞可為自體或同種異體的。自體是指來源於待治療患者的免疫細胞。同種異體是指來源於與待治療患者同種的另一個體的免疫細胞。
另外,免疫細胞可來源於人類誘導性富潛能幹細胞(iPSC)。與自體或同種異體免疫細胞相比,來源於iPSC的免疫細胞可自我增殖。因此,其易於大量增殖,且可製備適用於所有人的通用細胞療法,且具有均質生產及成本降低的優點。
免疫細胞可藉由載體使用顯微注射、電穿孔、音振作用、生物射彈(例如基因槍)、脂質轉染、聚合物轉染、磷酸鈣沈澱、原生質體融合、脂質體介導的轉染、奈米顆粒或多複合體等方法進行轉染或轉導,但不限於此。
根據又一態樣,提供一種用於預防或治療癌症的組成物,所述組成物包含:黏蛋白1結合多肽;分離的多核苷酸,對黏蛋白1結合多肽進行編碼;載體,包含對黏蛋白1結合多肽進行編碼的多核苷酸;細胞,包含對黏蛋白1結合多肽進行編碼的多核苷酸;嵌合抗原受體,包含黏蛋白1結合多肽;分離的多核苷酸,對嵌合抗原受體進行編碼;載體,包含對嵌合抗原受體進行編碼的多核苷酸;或者免疫細胞,包含對嵌合抗原受體進行編碼的多核苷酸或對嵌合抗原受體進行表達。
根據又一態樣,提供一種預防或治療癌症的方法,所述方法包括給需要預防或治療癌症的患者施用:有效量的黏蛋白1結合多肽;對黏蛋白1結合多肽進行編碼的分離的多核苷酸;包含對黏蛋白1結合多肽進行編碼的多核苷酸的載體;包含對黏蛋白1結合多肽進行編碼的多核苷酸的細胞;包含黏蛋白1結合多肽的嵌合抗原受體;對嵌合抗原受體進行編碼的分離的多核苷酸;包含對嵌合抗原受體進行編碼的多核苷酸的載體;或者包含對嵌合抗原受體進行編碼的多核苷酸或對嵌合抗原受體進行表達的免疫細胞。
根據又一態樣,提供一種用於預防或治療癌症的組成物,所述組成物包含T細胞,所述T細胞包含含有黏蛋白1結合多肽的嵌合抗原受體。
根據又一態樣,提供一種預防或治療癌症的方法,所述方法包括給需要預防或治療癌症的患者施用有效量的T細胞,所述T細胞包含含有黏蛋白1結合多肽的嵌合抗原受體。
舉例而言,癌症可為實體癌或血癌。其非限制性實例可包括乳腺癌、肺癌、前列腺癌、卵巢癌、腦癌、肝癌、宮頸癌、子宮內膜癌、子宮癌、結腸癌、結腸直腸癌、直腸癌、腎癌、腎母細胞瘤、皮膚癌、口腔鱗狀細胞癌、表皮樣癌、鼻咽癌、頭頸癌、骨癌、食道癌、膀胱癌、淋巴瘤(例如霍奇金淋巴瘤(Hodgkin’s lymphoma)或非霍奇金淋巴瘤)、胃癌、胰腺癌、睾丸癌、甲狀腺癌、濾泡狀癌、黑色素瘤、骨髓瘤、多發性骨髓瘤、間皮瘤、骨肉瘤、骨髓增生異常綜合征、間葉源性腫瘤、軟組織肉瘤、脂肪肉瘤、胃腸間質肉瘤、惡性周邊神經鞘腫瘤(malignant peripheral nerve sheath tumor,MPNST)、尤文氏肉瘤、平滑肌肉瘤、間葉軟骨肉瘤、淋巴肉瘤、纖維肉瘤、橫紋肌肉瘤、畸胎瘤、神經母細胞瘤、髓母細胞瘤、神經膠質瘤、良性皮膚腫瘤或白血病。肺癌可為例如小細胞肺癌(small cell lung carcinoma,SCLC)或非小細胞肺癌(non-small cell lung carcinoma,NSCLC)。白血病可為例如急性髓細胞性白血病(acute myeloid leukemia,AML)、慢性髓細胞性白血病(chronic myelogenous leukemia,CML)、急性淋巴細胞性白血病(acute lymphocytic leukemia,ALL)或慢性淋巴細胞性白血病(chronic lymphocytic leukemia,CLL)。
較佳為,所述癌症可為MUC1蛋白表達癌症,且可為乳腺癌、皮膚癌、胰腺癌、前列腺癌、肺癌、甲狀腺癌、胃癌、卵巢癌、結腸直腸癌、肝癌、膽囊癌、腎癌、宮頸癌或膀胱癌,但不限於此。癌症可為原發性癌症或轉移性癌症。
待治療的患者可為接受二級抗過度增殖療法的患者。舉例而言,二級抗過度增殖療法可為化學療法、放射療法、免疫療法、光線療法、冷凍療法、毒素療法、激素療法或手術。
使用包含含有本揭露的黏蛋白1結合多肽的嵌合抗原受體的T細胞的CAR-T抗癌療法可藉由一系列流程執行,包括:自健康人或待治療患者的血液提取T細胞;對T細胞進行基因工程改造以表達包含本揭露黏蛋白1結合多肽的嵌合抗原受體;對改造的T細胞進行擴增及培養,並將如此培養的改造的T細胞向患者施用。
在較佳的實施例中,自健康人或待治療患者的血液提取T細胞的步驟可藉由在使用白細胞去除術或除去術(aphresis)自血液分離白細胞並富集T細胞後提取T細胞來執行。可在CD4/CD8組成物水準下使用特異性抗體珠接合(specific antibody bead conjugate)或標記來對T細胞進行分離。作為另外一種選擇,亦可藉由自幹細胞分化來穩定地獲得大量T細胞。
本揭露中提供的對提取的T細胞進行基因工程改造以表達嵌合抗原受體的步驟可藉由例如使用載體(例如病毒載體(慢病毒載體、逆轉錄病毒載體等))將設計成對嵌合抗原受體(CAR)進行表達的核苷酸分子注射至T細胞中來執行。CAR可以DNA的形式引入,或者CAR可以RNA的形式引入,然後RNA藉由逆轉錄酶逆轉錄成可整合至T細胞的基因組中的DNA。另外,在同種異體細胞療法的情況下,可附加執行基因操縱以移除或糾正在供體T細胞中誘導移植排斥的基因,以防止排斥(例如移植物抗宿主疾病(graft-versus-host disease,GvHD))。
對改造的T細胞進行擴增及培養的步驟可藉由根據本領域中已知的培養技術對T細胞進行培養、增殖及擴增來執行。在此方面,需要針對病毒使用的安全性及用於選擇製作良好的CAR-T細胞的技術。
最後,向患者施用改造的T細胞的步驟可藉由例如輸注來執行。在較佳的實施例中,在CAR-T細胞注射前,患者可接受使用環磷醯胺或氟達拉濱進行的淋巴細胞刪除化療,以降低白細胞水準。另外,為提高CAR-T細胞的持久性,可一起施用細胞因子(例如IL-2)。
對患者施用的改造的T細胞可介導針對表達黏蛋白1的腫瘤細胞的免疫反應。該些免疫反應包括T細胞的活化、由T細胞進行的細胞因子(例如,IL-2及IFN-γ)分泌、識別腫瘤抗原的T細胞的增殖及擴增、以及T細胞介導的對靶陽性細胞的特異性殺傷(腫瘤的移除)。舉例而言,當CAR與CAR-T細胞中的黏蛋白1特異性結合時,T細胞藉由CD3ζ的免疫受體酪胺酸系激活基序(ITAM)的磷酸化而被激活,且隨後可誘導T細胞增殖、細胞毒性及/或細胞因子分泌。
如上所述,使用CAR-T細胞的抗癌療法在根本上激活患者的免疫系統,並發揮持續的抗癌效果,且因此其優點在於不需要繼續給藥,且藉由使用患者自身的T細胞可進行個性化治療。
本揭露的組成物的給藥可引起、誘導或促進對疾病發作或進展進行抑制、停止、延遲或防止的免疫反應。
用語「有效量」是指當對受試者(包括人)施用時,足以達到所需結果的量,例如有效治療或預防癌症的量。有效量可依據各種因素(例如配製方法、給藥方式、患者年齡、體重、性別、疾病嚴重程度、飲食、給藥時間、給藥途徑、排泄率及反應敏感性)而變化。如熟習此項技術者將理解的,可對給藥劑量或治療制度進行調節以提供最佳的治療反應。
具有治療有效量的治療制度可由單劑量給藥組成,或者作為另外一種選擇,可包括一系列應用。治療階段的持續時間由各種因素(例如,製劑方法、給藥方式、患者年齡、體重、性別、疾病嚴重程度、飲食、給藥時間、給藥途徑、排泄率及反應敏感性)決定。亦應理解,在個體治療制度的過程期間,用於治療的抗癌組成物的有效劑量可增加或降低。可能發生劑量的變化,且所述變化藉由本領域中已知的標準診斷分析將是顯而易見的。在某些態樣中,本發明的組成物可在使用普通抗癌劑、放射療法、激素療法、生物療法及/或腫瘤手術切除進行治療之前、期間或之後施用。
本揭露的組成物可與一或多種添加劑一起提供,所述一或多種添加劑選自由藥學上可接受的運載體、稀釋劑及賦形劑組成的群組。
通常用於抗體製劑中的藥學上可接受的運載體可為選自由以下組成的群組中的一或多種:乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、澱粉、阿拉伯樹膠、磷酸鈣、藻酸鹽、明膠、矽酸鈣、微晶纖維素、聚乙烯吡咯啶酮、纖維素、水、糖漿、甲基纖維素、甲基羥基苯甲酸酯、羥基苯甲酸丙酯、滑石、硬脂酸鎂、礦物油等,但不限於此。除了以上組分之外,所述組成物可更包括選自由以下組成的群組中的一或多種:通常用於藥物組成物的製備中的稀釋劑、賦形劑、潤滑劑、濕潤劑、甜味劑、調味劑、乳化劑、懸浮劑、防腐劑等。
所述組成物可口服或腸胃外施用。當腸胃外施用時,可使用靜脈注射、皮下注射、肌肉注射、腹膜內注射、內皮給藥、局部給藥、鼻內給藥、肺內給藥及直腸給藥。當口服施用時,蛋白質或肽被消化,且因此可配製用於口服給藥的組成物來包覆活性劑或保護其在胃中不被降解。另外,所述組成物可藉由任何能夠將活性物質轉運至靶細胞的裝置施用。
可使用標準給藥技術、製劑或裝置來施用細胞。可適當使用用於組成物的儲存及給藥的製劑及裝置(例如注射器及小瓶)。細胞的給藥可為自體的、同種異體的或異種的。可藉由導管給藥、全身注射、局部注射、靜脈注射或包括腸胃外給藥的局部注射來施用來源於周邊血的免疫細胞或其後代(例如,來源於體內(
in vivo)、離體(
ex vivo)或體外(
in vitro))。當施用免疫細胞治療劑時,它們一般可被配製成可注射的單位劑型(溶液、懸浮液、乳液)。在一些實施例中,細胞群可胃腸外給藥。製劑包括用於靜脈注射、皮下注射、肌肉內注射、腹膜內注射、內皮給藥、局部給藥、鼻內給藥、肺內給藥及直腸給藥的製劑。
在一些實施例中,組成物作為無菌液體製劑(例如作為等滲水溶液、懸浮液、乳液、分散體或黏性組成物)提供,在一些態樣中,可將其緩衝至選定的pH。液體製劑通常較凝膠、其它黏性組成物及固體組成物更容易製備。另外,液體組成物特別便於藉由注射進行施用。另一方面,黏性組成物可在合適的黏度範圍內配製,以提供與特定組織更長的接觸時間。液體組成物或黏性組成物可包括運載體,所述運載體可為包含例如水、鹽水、磷酸鹽緩衝鹽水、多元醇(例如丙三醇、丙二醇、液體聚乙二醇)及其適當的混合物的溶劑或分散介質。
無菌注射溶液可藉由將結合分子摻入溶劑(例如與合適的運載體、稀釋劑或賦形劑(例如無菌水、生理鹽水、葡萄糖、右旋糖等)混合)中來製備。組成物亦可為凍乾的。依據給藥途徑及所需的製劑,組成物可包括輔助物質,例如潤濕劑、分散劑或乳化劑(例如甲基纖維素)、pH緩衝劑、膠凝或黏度增強添加劑、防腐劑、調味劑、著色劑等。
可添加增強組成物穩定性及無菌性的各種添加劑,包括抗微生物防腐劑、抗氧化劑、螯合劑及緩衝劑。藉由各種抗細菌及抗真菌劑(例如對羥基苯甲酸酯、氯丁醇、苯酚、山梨酸等)可確保防止微生物作用。可注射藥物形式的延長吸收可藉由使用延遲吸收的試劑(例如單硬脂酸鋁及明膠)來達成。
[實施例的詳細說明]
在下文中,將參照以下示例性實施例更詳細地闡述本發明。然而,該些示例性實施例僅用於對本發明進行例示,且本發明的範圍不受該些示例性實施例的限制。
實例 1. 製備與黏蛋白 1 結合的 scFv
將人黏蛋白1(SEQ ID NO: 110)與CD4(SEQ ID NO: 111)接合以製備重組抗原。自scFv資料庫篩選出分泌特定於抗原的scFv的克隆,並選擇與黏蛋白1特異性結合的10種scFv。如此選擇的10種scFv的序列資訊與隨後實驗中使用的陽性對照scFv G03(使用WO2018/174544的表6的G3抗體的胺基酸序列製備的陽性對照)示於表3中。
[表3]
[表4]
使用拜愛可(Biacore)T200(GE醫療(GE healthcare))對scFv-Fc抗體(包括scFv)對黏蛋白1抗原的親和力進行量測。在5微升/分鐘的速率下將抗人IgG(Fc)抗體(GE醫療,目錄編號BR-1008-39,最終濃度為25微克/毫升)施加於使用胺基偶聯試劑盒(GE醫療,目錄編號BR-1000-50)的S系列感測器晶片CM5(GE醫療,目錄編號BR-1005-30)上360秒,並在約5000约化单位(Reduced Unit,RU)至7000約化單位下固定化。以30微升/分鐘的速率以自25奈莫耳/升(nM)至400奈莫耳/升的五種不同濃度注射作為抗原的人MUC1蛋白,且獲得k
a值及k
d值,如下表中所示,並由此計算K
D值。因此,表示對黏蛋白1的結合親和力的K
D(M)值如表5中所示。
[表5]
實例 2. 使用與黏蛋白 1 結合的 scFv 製備 CAR - T 細胞 2-1. 表達 CAR 的慢病毒轉移載體的製備
克隆 名稱 | scFv 胺基酸序列 |
2445_1F09 | EVQLLETGGGLIQPGGSLRLSCAASGFTVSSNYMSWVRQAPGKGLEWVSVIYSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRGWNHGMDVWGQGTLVTVSSGGGGSGGGGSGGGASQSGLTQPPSASGTPGQRVTISCSGGSSEVGSRYVSWYQQLPGTAPRLLIYKNDRRPSGVPDRFSGSKSGSSASLAISGLRSEDEADYYCAAWDDSLNGYVFGTGTKLTVL (SEQ ID NO: 9) |
2447_2H08 | EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDPHILTGYYRGGWFDPWGQGTTVTVSSGGGGSGGGGSGGGASSYELTQDPAVSVALGQTVTITCQGDSLRTSYAGWLQQKPGQAPVLVLYGKTSRPSGIPDRFSGSTSGNTASLTITGAQAEDEAEYFCHSRDSNDNYLEVVFGGGTKLTVL (SEQ ID NO: 19) |
2447_3A01 | EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIVYADFVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDISSGWYPGTFDYWGQGTLVTVSSGGGGSGGGGSGGGASSYELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTVTGAQAEDEADYYCSSRDSSDDVVFGGGTQLTVL (SEQ ID NO: 29) |
2447_3A08 | EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDRATIFGVVTPFDYWGQGTLVTVSSGGGGSGGGGSGGGASSYELTQDPAVSVALGQTVRITCQGDSIRSYSASWYQQKPGQAPRLVIYGKNNRPSGIPDRVSGSTSGNTASLTVTGAQAEDEADYYCNSRDSSGNRVVFGGGTQLTVL (SEQ ID NO: 39) |
2447_3A09 | EVQLLESGGGLVQPGRSLRLSCAATGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTASYYCAKDVSSGWYWYAFDIWGQGTLVTVSSGGGGSGGGGSGGGASSYELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPGRFSGSSSGNTASLTVTGAQAEDEADYYCNSRDSGGSVVFGGGTKLTVL (SEQ ID NO: 49) |
2447_3A12 | EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLRGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDPHILTGYYRGGWFDPWGQGTLVTVSSGGGGSGGGGSGGGASSYELTQDPAVSVVLGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDSSGNHRVFGGGTKLTVL (SEQ ID NO: 59) |
2447_3B07 | QVQLVESGGVVVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGRGLEWVSLTSWDGGSTYYADSVKGRFTISRDNSKNSLYLQMNSLRAEDTALYYCAKDHSSGWYNGGMDVWGQGTMVTVSSGGGGSGGGGSGGGASSYELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDSSGNHVVFGGGTKLTVL (SEQ ID NO: 69) |
2447_3C08 | EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDRGSGYEGNYYGMDVWGQGTLVTVSSGGGGSGGGGSGGGASSYELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGTTSGNTASLTITGAQAEDEADYYCNSRDSSGNHYVFGTGTKVTVL (SEQ ID NO: 79) |
2447_3H02 | EVQLLESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWDSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDVSSGWYWYAFDIWGQGTLVTVSSGGGGSGGGGSGGGASSYELTQDPAVSVALGQTVRITCQGDILRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDSSGNRVVFGGGTKLTVL (SEQ ID NO: 89) |
2447_3H08 | EVQLLESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRSSGWYTGSFDYWGQGTLVTVSSGGGGSGGGGSGGGASSYELTQDPAVSVALGQTVRITCQGDSLRSYYASWYRQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTIIGAQAEDEADYYCQSRDSSDNRVLFGGGTKVTVL (SEQ ID NO: 99) |
G03 | EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMHWVQQAPGKGLEWIGYINPGTGYIEYNQKFKDRVTITADKSTDTAYMELSSLRSEDTAVYYCASSTAPFDYWGQGTLVTVSSGGGGSGGGGSGGGASEIVLTQSPGTLSLSPGERATLSCKASQDIKSYLSWYQQKPGQAPRLLIYYATRLADGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCLQYDESPYTFGQGTKLEIK (SEQ ID NO: 109) |
克隆 名稱 | scFv 核苷酸序列 |
2445_1F09 | GAGGTGCAGCTGTTGGAGACTGGAGGAGGCTTGATCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCACCGTCAGTAGCAACTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTTATAGCGGTGGTAGCACATATTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAGAGATCGCGGCTGGAACCACGGTATGGACGTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCCAGTCTGGGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGTTCTGGGGGCAGCTCAGAAGTCGGAAGTAGATATGTGTCCTGGTACCAGCAACTCCCAGGAACGGCCCCCAGACTCCTCATCTATAAGAATGATCGGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCTCCTCAGCCTCCCTGGCCATCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAATGGTTATGTCTTCGGAACTGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 10) |
2447_2H08 | GAAGTGCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAACTACGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGCTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATCCGCATATTTTGACTGGTTATTATAGGGGAGGGTGGTTCGACCCCTGGGGGCAAGGGACCACGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCTCCTATGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGTCAGACAGTCACCATCACGTGCCAAGGAGACAGCCTCAGAACCTCTTATGCAGGCTGGCTCCAGCAGAAGCCAGGACAGGCCCCTGTACTCGTCCTCTATGGTAAAACCAGCCGGCCCTCAGGGATCCCAGACCGATTCTCTGGCTCCACCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAGGATGAGGCTGAGTATTTCTGTCACTCCCGGGACAGCAATGATAACTATCTAGAGGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 20) |
2447_3A01 | GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGTGGTAGCATAGTCTATGCGGACTTTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAAGATATTTCAAGTGGCTGGTACCCAGGGACCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCTCCTATGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGAAGCTATTATGCAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTACTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCGTCACTGGGGCTCAGGCGGAAGACGAGGCTGACTATTACTGTAGCTCCCGGGACAGCAGTGATGATGTGGTATTCGGCGGAGGGACCCAGCTCACCGTCCTA (SEQ ID NO: 30) |
2447_3A08 | GAAGTGCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAGCTACGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGCTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATCGGGCTACGATTTTTGGAGTGGTTACCCCCTTTGACTACTGGGGCCAAGGAACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCTCCTATGAGCTGACTCAGGACCCCGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATCACATGCCAGGGAGACAGTATTAGAAGTTATTCTGCCAGCTGGTACCAGCAGAAGCCAGGGCAGGCCCCTCGCCTTGTTATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGAGTCTCTGGCTCCACTTCAGGAAATACAGCTTCCTTGACCGTCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTGTAACTCCCGGGACAGCAGTGGTAACCGTGTGGTATTCGGCGGAGGGACCCAGCTCACCGTCCTA (SEQ ID NO: 40) |
2447_3A09 | GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCAGCCACTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGTGGTAGCATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTCGTATTACTGTGCAAAAGATGTTAGCAGTGGCTGGTACTGGTATGCTTTTGATATCTGGGGCCAAGGAACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCTCCTATGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGAAGCTATTATGCAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTACTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGGCCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCGTCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTGTAATTCCCGGGACAGCGGTGGTTCTGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 50) |
2447_3A12 | GAAGTGCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAGCTATGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGCTCCGGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATCCGCATATTTTGACTGGTTATTATAGGGGAGGGTGGTTCGACCCCTGGGGCCAGGGCACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCTCCTATGAGCTGACTCAGGACCCTGCTGTGTCTGTGGTCTTGGGACAGACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGAAGCTATTATGCAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTACTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTGTAACTCCCGGGACAGCAGTGGTAACCATCGTGTATTCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 60) |
2447_3B07 | CAGGTGCAGCTGGTGGAGTCTGGGGGAGTCGTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGTCAAGCTCCGGGGAGGGGTCTGGAGTGGGTCTCTCTTACTAGTTGGGATGGTGGTAGCACATACTATGCAGACTCTGTGAAGGGTCGATTCACCATCTCCAGAGACAACAGCAAAAACTCCCTGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACCGCCTTGTATTACTGTGCAAAAGATCATAGCAGCGGCTGGTACAACGGGGGTATGGACGTCTGGGGCCAAGGGACAATGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCTCCTATGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGAAGCTATTATGCAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTACTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTGTAACTCCCGGGACAGCAGTGGTAACCATGTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 70) |
2447_3C08 | GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGTGGTAGCATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAAGATAGGGGTAGTGGCTACGAAGGAAACTACTACGGTATGGACGTCTGGGGCCAAGGAACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCTCCTATGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGAAGCTATTATGCAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTACTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGTACCACCTCAGGAAACACAGCCTCCTTGACCATCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTGTAACTCCCGGGACAGCAGTGGTAACCATTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA (SEQ ID NO: 80) |
2447_3H02 | GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGGATAGTGGTAGCATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAAGATGTTAGCAGTGGCTGGTACTGGTATGCTTTTGATATCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCTCCTATGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATCACATGCCAAGGAGACATCCTCAGAAGTTATTATGCAAGTTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTACTTGTCATTTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTGTAACTCCCGGGACAGCAGTGGTAACCGTGTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 90) |
2447_3H08 | GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGTGGTAGCATAGACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACAGCTGTGTACTACTGTGCGAGAGATCGGAGTAGTGGCTGGTACACGGGGTCCTTTGACTACTGGGGCCAGGGCACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCTCCTATGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGAAGCTATTATGCAAGCTGGTACCGGCAGAAGCCAGGACAGGCCCCTGTACTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGCTCCAGCTCGGGAAACACAGCTTCCTTGACCATCATTGGGGCTCAGGCGGAAGACGAGGCTGACTATTACTGTCAGTCCCGGGACAGCAGTGATAACCGTGTTCTATTCGGCGGAGGGACCAAGGTCACCGTCCTA (SEQ ID NO: 100) |
克隆名稱 | K D ( M ) |
2447_2H08 | 94.8 x 10 -9 |
2447_3A01 | 51.5 x 10 -9 |
2447_3A08 | 320.3 x 10 -9 |
2447_3A09 | 62.1 x 10 -9 |
2447_3A12 | 13.8 x 10 -9 |
2447_3B07 | 51.7 x 10 -9 |
2447_3C08 | 24.0 x 10 -9 |
2447_3H02 | 58.8 x 10 -9 |
2447_3H08 | 39.9 x 10 -9 |
G03 | 27.6 x 10 -9 |
製備對嵌合抗原受體(CAR)進行表達的慢病毒載體(轉移載體或表達載體),所述嵌合抗原受體包含含有scFv多肽序列(表4的核苷酸序列)的細胞外域、鉸鏈(CD8α)(SEQ ID NO: 112)及跨膜域(CD28)(SEQ ID NO: 113)、共刺激域(CD28)(SEQ ID NO: 114)以及細胞內傳訊域(CD3ζ)(SEQ ID NO:115)。藉由聚合酶連鎖反應(polymerase chain reaction,PCR)自篩選公司提供的質粒中分離出CAR的scFv區,並藉由PCR自合成的質粒中分離出鉸鏈、跨膜蛋白以及CD28傳訊域及CD3z傳訊域。使用寶生物(Takara)的In-Fusion HD克隆試劑盒將兩個片段克隆至克隆科技(Clonetech)的pLVX-EF 1α載體中。將如此克隆的慢病毒載體與由同一公司的倫蒂(Lenti)-X表達系統(EF1a版本)(產品碼631253)提供的包裝質粒一起轉染至寶生物的倫蒂-X 293T細胞系(產品碼632180)中,且在24小時後對湯汁進行分離,且將其中的慢病毒用於進一步研究。
2-2. 慢病毒顆粒的生產
為了生產慢病毒,使用脂質體核酸轉染試劑(脂質體,吉比科(Gibco))將上面製備的慢病毒轉移載體(轉移載體或表達載體)及包裝質粒混合物轉染至倫蒂-X 293T細胞(寶生物產品編號632180)中。在轉染前一天,在約6%至70%的培養板面積的匯合處製備HEK293T細胞。使用補充有10%熱滅活胎牛血清(FBS,吉比科)的達爾伯克氏改良伊格爾培養基(Dulbecco’s modified Eagle medium)(DMEM,吉比科)作為培養基,並使用100毫米或150毫米大小的培養板。將培養條件維持在37℃、5% CO
2及濕潤條件下。根據製造商的指示,藉由調節它們的比率,在室溫下將轉移載體、慢病毒包裝質粒混合物及脂質體核酸轉染劑混合,並在培養期間滴在板上的HEK293T細胞上,以轉染HEK293T細胞。轉染後,HEK293T細胞中產生的慢病毒自細胞爆發出來,並以病毒顆粒的形式存在於細胞培養物中。轉染後48小時,僅自培養板移除細胞培養液,並進行離心以獲得丸形式的慢病毒顆粒。使用溶液使丸懸浮,然後將所述溶液立即使用或儲存於低溫冷凍器中。作為溶液,使用上面使用的DMEM培養基,或使用以下溶液:所述溶液藉由將最佳化器T-細胞擴增補充劑(26毫升)添加至T細胞培養中使用的細胞治療系統(cell therapy system,CTS)最佳化器T細胞擴增SFM(吉比科)的1升瓶中,添加最終濃度為2%的CTS免疫細胞(Immune Cell)血清替代物(Serum Replacement)(SR,吉比科),且然後添加終濃度為1X的CTS GlutaMAX-I補充劑100X(吉比科)來製備。
2-3. CAR-T 細胞的製備
藉由與韓國天主教大學(Catholic University of Korea)的研究協議提供周邊血單核細胞(PBMC)樣本,並在韓國天主教大學-制度審查委員會(Institutional Review Board)的批準下實行供體招募及血液採集。所有的血均為正常人的。在本揭露的示例性實施例中,「供體」是指實驗中使用的PBMC樣品的供體,且供體之後的數字是指供體不同(例如,由供體03、供體04、供體05、供體06、供體07、供體08、供體18-09、供體20-01等表示)。為製備在T細胞表面對嵌合抗原受體(CAR)進行表達的CAR-T細胞,將冷凍的PBMC小瓶在37℃下在水浴中解凍。在冷凍的PBMC解凍後的第二天,對細胞數進行計數,隨後使用新鮮培養基進行替換。同時,使用T細胞特異性擴增珠(免疫磁珠(Dynabeads)人T擴增器CD3/CD28,吉比科)激活T細胞,並藉由根據激活細胞的數目對T細胞進行處理來轉導慢病毒形式的嵌合抗原受體(CAR)。為了培養轉導的T細胞,基於培養基的量,以100國際單位(IU)/毫升添加白細胞介素-2(諾華(Norvatis))在過濾無菌蒸餾水中的懸浮液,且在隨後的培養期間,當更換或添加培養基時,連續地添加懸浮液。細胞培養期在活化後總共為10天至11天,且在依據細胞數目每1至2天更換或新添加培養基的同時執行細胞培養。在培養期結束時,完成細胞培養,且完成CAR-T細胞生產。將製備的CAR-T細胞立即使用,或者與細胞冷凍保存溶液混合,並注射至用於細胞冷凍的小瓶中並儲存在液氮罐中。藉由流式細胞術(flow cytometry,FACS)對製備的CAR-T細胞的嵌合抗原受體(CAR)的表達水準及其特性進行分析。
實例 3. 可溶性 scFv 對表達黏蛋白 1 的細胞的親和力分析
在下文中,除非另有說明,否則在本示例性實施例中使用的細胞系的資訊如下:
-PANC-1;韓國細胞系庫(Korean Cell Line Bank),21469
-HCC1954;韓國細胞系庫,9S1954
-HCC70;韓國細胞系庫,9S0070
-T47D;韓國細胞系庫,30133
-HEK293T;ATCC,CRL-3216
-Huh7;韓國細胞系庫,60104
-HepG2;ATCC,HB-8065
-SK-N-SH;韓國細胞系庫,30011
在實例3中使用總共4種細胞系,且其中,HEK293(美國典型培養物保藏中心(American type culture collection,ATCC))及PANC-1(ATCC)細胞系用作陰性對照,且HEK293T-v1 (ATCC,且由LG化學(LG Chem)轉化)及T47D(韓國細胞系庫)用作陽性對照。用作陽性對照的HEK293T-v1細胞系是藉由在不表達黏蛋白1的HEK293T細胞系中表達MUC1的C亞基而獲得的細胞系。使用11種類型的scFv,且其中,陽性對照是G03(表3)。將實例1中製備的可溶性scFv稀釋5倍,以製備總共8個系列稀釋液。每一系列稀釋度為380微克/毫升、76微克/毫升、15.2微克/毫升、3.04微克/毫升、0.608微克/毫升、0.1216微克/毫升、0.02432微克/毫升、0.004864微克/毫升。用於可溶性scFv稀釋及細胞清洗的緩衝液是含有2% FBS及10毫莫耳/升(mM)乙二胺四乙酸(Ethylene Diamine Tetraacetic Acid,EDTA)的磷酸鹽緩衝液(phosphate buffer saline,PBS)。分別以1×10
6/毫升的密度製備四種細胞,且以1×10
5/100微升/孔的密度置於96孔U形底細胞培養板中,隨後以1500轉/分鐘(revolutions per minute,RPM)離心達5分鐘。以50微升/孔的量對先前製備的可溶性scFv進行處理。將細胞在4℃下放置1小時。向其中添加150微升/孔的細胞清洗緩衝液,且然後进行混合,隨後以1500轉/分鐘離心達5分鐘。棄去上清液,且向其中添加200微升/孔的細胞清洗緩衝液,且然後进行混合,隨後以1500轉/分鐘離心達5分鐘。將山羊抗人IgG Fc-生物素抗體(英傑(Invitrogen),A18821)稀釋500倍,且以其50微升/孔進行處理。將細胞在4℃下放置20分鐘。向其中添加150微升/孔的細胞清洗緩衝液,且然後進行混合,隨後以1500轉/分鐘離心達5分鐘。棄去上清液,且向其中添加200微升/孔的細胞清洗緩衝液,且然後進行混合,隨後以1500轉/分鐘離心達5分鐘。將藻紅蛋白(phycoerythrin,PE)-鏈黴親和素(碧迪費明根(BD Pharmigen),554061)稀釋1000倍,且以其50微升/孔進行處理。將細胞在4℃下放置20分鐘。向其中添加150微升/孔的細胞清洗緩衝液,且然後進行混合,隨後以1500轉/分鐘離心達5分鐘。棄去上清液,且向其中添加200微升/孔的細胞清洗緩衝液,且然後混合,隨後以1500轉/分鐘離心達5分鐘。添加80微升/孔的細胞清洗緩衝液並混合,隨後進行流式細胞術。
可溶性scFv對表達黏蛋白1的細胞的親和力根據流式細胞術的結果由PE平均螢光強度(mean fluorescence intensity,MFI)值得到確認。不具有可溶性scFv的每一細胞系使用另一種螢光抗體(山羊抗人IgG Fc-生物素抗體,PE-鏈黴親和素)染色,將其用作陰性對照值,且每一細胞系使用濃度為380微克/毫升的G03進行處理,用作陽性對照值,且MFI值校正如下:
(實驗值-陰性對照值)/(陽性對照值-陰性對照值)×100=實驗值的校正值
使用校正值計算EC
50,且所述結果是用作陽性對照的兩種細胞系的結果(表6)。
[表6]
實例 4. CAR-T 細胞分泌細胞因子的分析
克隆名稱 | EC 50 ( 293T-v1 )( ug/ml ) | EC 50 ( T47D )( ug/ml ) |
G03 | 3.46 | 3.56 |
2445_1F09 | 1.51x10 7 | 6.19x10 7 |
2447_3A01 | 4.78 | 11.14 |
2447_3A08 | 1.73 | 3.76 |
2447_3A09 | 1.96 | 2.2 |
2447_3A12 | 1.47 | 0.75 |
2447_3C08 | 1.38 | 2.04 |
2447_3H02 | 1.41 | 1.6 |
2447_3H08 | 2.57 | 5.6 |
2447_2H08 | 21.73 | 130.4 |
2447_3B07 | 3.86 | 3.47 |
對其中以CAR形式注射抗MUC1 scFv的免疫細胞(T細胞)對MUC1陽性腫瘤細胞(T47D,HEK293T-V1)的反應進行評估。將天然表達高水準MUC1的T47D細胞及過表達人MUC1 C亞基的HEK293T-V1細胞與根據實例2製備的總共10種免疫細胞2445_1F09、2447_3A01、2447_3A08、2447_3A09、2447_3A12、2447_3C08、2447_3H02、2447_3H08、2447_2H08、2447_3B07共培養(在一些圖式中,分别縮寫為1F09、3A01、3A08、3A09、3A12、3C08、3H02、3H08、2H08、3B07),其中以1:1.5的腫瘤細胞:免疫細胞的比率以CAR的形式注射抗MUC1 scFv達24小時。藉由酶聯反應吸附測定(enzyme-linked immuno sorbent assay,ELISA)檢查由其獲得的培養基中兩種細胞因子、即干擾素-γ(interferon-gamma,IFNg)及白細胞介素-2(interleukin-2,IL-2)的濃度。以與通常使用的方法相同的方式執行ELISA,且簡概如下。首先,使用能夠捕獲干擾素-γ或白細胞介素-2的捕獲抗體來塗佈96孔板。1天后,使用清洗緩衝液對平板進行充分清洗。向每個孔添加封閉緩衝液,且在室溫下放置1小時,隨後使用清洗緩衝液進行充分清洗。為了知道絕對值,連同已知濃度的標準溶液,向每一孔添加培養溶液樣品,在室溫下放置2小時,且使得能夠反應。使用清洗緩衝液對板進行充分清洗,且然後向其中添加檢測抗體,並使其能夠在室溫下反應2小時。使用清洗緩衝液對板進行充分清洗,且然後向每一孔添加辣根過氧化物酶(horseradish peroxidase,HRP)-接合的鏈黴親和素,並使其能夠在室溫下反應20分鐘。使用清洗緩衝液對板進行充分清洗,且然後添加基底溶液,並使其能夠在室溫下反應20分鐘。使用終止溶液終止反應。根據反應藉由吸光度計算每一孔中的細胞因子濃度。
在圖1中,G03表示陽性對照,且作為陰性對照,使用其中未注射CAR的組(無LV)。另外,圖1顯示示出使用總共兩種T細胞的獨立實驗結果的代表性曲線圖,其中根據T細胞的來源將它們命名為供體03及供體04。在本示例性實施例中,「供體」是指實驗中使用的T細胞的供體,且供體後的數字表示供體不同。圖1顯示基於對照G03其中吸光度被標準化的圖,顯示測試的免疫細胞分泌細胞因子。
圖2顯示對免疫細胞(其中以CAR的形式向免疫細胞中注射抗MUC1 scFv)針對MUC1陽性腫瘤細胞(T47D)的反應進行評估的細胞因子分泌分析的結果,顯示測試的免疫細胞分泌細胞因子。T細胞來源於供體06。將其中未注射CAR的組(對照T細胞)用作陰性對照。
圖3顯示對免疫細胞(其中以CAR的形式向免疫細胞中注射抗MUC1 scFv)針對不表達黏蛋白1的細胞(HEK293T)的反應進行評估的細胞因子分泌分析的結果,顯示與陰性對照(對照T細胞)的免疫細胞相比,免疫細胞不分泌干擾素γ細胞因子,且IL-2的分泌量沒有顯著增加。T細胞來源於供體06。將其中未注射CAR的組(對照T細胞)用作陰性對照。
實例 5. CAR-T 細胞的細胞毒性分析
人乳腺癌細胞系(T47D、HCC70、HCC1954)、人肝癌細胞系(Huh7、HepG2)及人成神經細胞瘤細胞系(SK-N-SH)購自韓國細胞系庫(KCLB,韓國首爾),且人胚胎腎細胞系(HEK293T)購自美國典型培養物保藏中心(ATCC,弗吉尼亞州,馬納薩斯)。T47D、HCC70及HCC1954細胞分別在RPMI-1640培養基(賽默飛世爾科技(Thermo Fisher Scientific))中培養,且HEK293T、Huh7及HepG2分別在杜爾貝科氏改良伊格爾培養基(DMEM,賽默飛世爾科技)中培養。所有培養基在補充10%(w/v)熱滅活胎牛血清(FBS,賽默飛世爾科技)後使用。所有細胞在37℃及5% CO
2的條件下培養。在37℃及5% CO
2的條件下,在CTS完全培養基(CTS™最佳化器(OpTmizer)™ T細胞擴增無血清培養基(serum free medium,SFM)(吉比科,A1048501)、2%(w/v)CTS™免疫細胞SR(吉比科,A25961-01)、1X GlutaMAX™補充劑(吉比科,35050-061))中培養根據實例2製備的CAR-T細胞。
為了對CAR-T細胞的黏蛋白1特定細胞毒性進行分析,藉由以下方法來量測表達黏蛋白1的細胞(包括T47D、HCC70、HCC1954、HEK293T-V1(外源性MUC1-C表達細胞)等)及不表達黏蛋白1的細胞(包括HEK293T、HepG2、Huh7、SK-N-SH等)的細胞裂解。首先,以0.15×10
6細胞/150微升/孔至0.2×10
6細胞/150微升/孔的密度對使用賽爾特雷斯(CellTrace)™羧基螢光素二醋酸鹽琥珀醯亞胺脂(5,6-carboxyfluorescein diacetate succinimidy ester,CFSE)(英傑,C34554)染色的表達黏蛋白1的靶細胞或不表達黏蛋白1的靶細胞進行分配,並培養一天。在同一天,將在-196℃下冷凍並儲存的CAR-T細胞解凍,並在含有30 U/毫升IL-2的CTS完全培養基(諾華,阿地白介素(Proleukin))中以2×10
6細胞/毫升的密度培養一天。第二天,藉由使用亞曆克莎弗洛爾(Alexa Fluor)488-阿菲尼皮爾(AffiniPure)山羊抗人IgG、F(ab’)2片段特異性(傑克森實驗室(Jackson laboratory),109-545-097)及APC小鼠抗人CD3(碧迪費明根™,561811)染色,並使用流式細胞術(FACS)獲得兩者的陽性細胞百分比,來量測培養期間CAR-T細胞的CAR表達率。使用每種靶細胞的細胞培養基以100微升/孔的體積製備CAR-T(E,效應細胞)的每種類型,基於CAR表達率將其調節至具有相同數目的CAR+ T細胞,並與前一天培養的表達黏蛋白1的CFSE染色細胞或不表達黏蛋白1的CFSE染色細胞(T,靶細胞)的數目成比例添加。依據靶細胞,在37℃、5% CO
2的條件下將細胞培養5小時至24小時。此後,取出所有CAR-T細胞及靶細胞,並使用可固定的活性染料艾芙洛尔(eFluor)™ 450(愛寶科學(eBioscience)™,65-0863-18)、APC小鼠抗人CD3染色。然後,使用流式細胞術獲得活靶細胞的數目。在此方面,活靶細胞的數目藉由可固定的活力染料陰性、CFSE陽性細胞確定。殺傷活性(%)藉由以下方程計算:
殺傷活性=100-(在(
T 細胞+
靶細胞)孔中活靶細胞的數目/在(
靶細胞)孔中活靶細胞的數目×100)(%)
結果如圖4至圖8中所示。在圖式中,G03代表陽性對照,且作為陰性對照,使用其中未注射CAR的組(無LV)。此外,該些圖式顯示示出使用總共兩種T細胞的獨立實驗結果的代表性曲線圖,其中根據T細胞的來源將它們命名為供體03及供體04。如圖4至圖8中所示,測試的免疫細胞表現出針對表達黏蛋白1的細胞的細胞毒性。
圖9及圖10顯示藉由使用來源於供體05及來源於供體06的T細胞製備的CAR-T細胞針對人乳腺癌細胞系T47D的細胞毒性的實驗結果,圖11顯示藉由使用來源於供體07的T細胞製備的CAR-T細胞針對人胚胎腎細胞系HEK293T的細胞毒性的實驗結果,且圖12顯示藉由使用來源於供體08的T細胞製備的CAR-T細胞針對人乳腺癌細胞系HCC70的細胞毒性的實驗結果。如圖9至圖12中所示,測試的免疫細胞表現出針對表達黏蛋白1的細胞的細胞毒性。
實例 6. CAR-T 細胞特定於黏蛋白 1 的細胞毒性分析
為了檢查CAR-T細胞是否能夠根據抗原量的差異來區分正常細胞與癌細胞,乳腺癌細胞系(HCC70)及人正常乳腺細胞系(MCF10A)的細胞裂解如下量測:首先,使用不同濃度的賽爾特雷斯(CellTrace)™ CFSE(英傑,C34554)分別對過表達黏蛋白1的HCC70細胞及表達低水準的黏蛋白1的MCF10A細胞進行染色,並以不同比率混合。HCC70:MCF10A的比率為0:0.2、0.025:0.175、0.05:0.15、0.075:0.125、0.1:0.1、0.125:0.075、0.15:0.05、0.175:0025、0.2:0。以0.2×10
6細胞/500微升/孔的密度對以預定比率混合的細胞進行分配,並培養一天。同一天,將在-196℃下冷凍及儲存的CAR-T細胞(對含有2447_2H08 scFv的CAR進行表達的來源於供體05的T細胞)解凍,並在含有30 U/毫升IL-2(諾華,阿地白介素)的CTS完全培養基中以2×10
6細胞/毫升的密度培養一天。第二天,藉由使用亞曆克莎弗洛爾488-阿菲尼皮爾山羊抗人IgG、F(ab’)2片段特異性(傑克森實驗室,109-545-097)及APC小鼠抗人CD3(碧迪費明根™,561811)染色,並使用流式細胞術(FACS)獲得兩者的陽性細胞百分比,來量測培養期間CAR-T細胞的CAR(含有2447_2H08 scFv的CAR)表達率。使用每種靶細胞的細胞培養基以100微升/孔的體積製備CAR-T(E,效應細胞)的每種類型,基於CAR表達率將其調節至具有相同數目的CAR+ T細胞,並與前一天培養的表達黏蛋白1的CFSE染色細胞或不表達黏蛋白1的CFSE染色細胞(T,靶細胞)的數目成比例添加。在37℃、5% CO
2的條件下將細胞在靶細胞中培養24小時。此後,取出所有CAR-T細胞及靶細胞,並使用可固定的活性染料艾芙洛爾™ 450(愛寶科學™,65-0863-18)、APC小鼠抗人CD3染色。然後,使用流式細胞術獲得活靶細胞的數目。在此方面,活靶細胞的數目由可固定的活力染料陰性、CFSE陽性細胞確定(HCC70由強CFSE訊號確定,且MCF10A由弱CFSE訊號確定)。以與實例5中相同的方式計算殺傷活性(%)。
結果如圖13及圖14中所示。在圖式中,作為陰性對照,使用其中沒有注射CAR的組(仿T細胞)。如圖13至圖14中所示,具有2447_2H08 scFv的CAR-T細胞(在圖式中,每一者由#2-CAR-T表示)表現出針對過表達黏蛋白1的乳腺癌細胞系(HCC70)的細胞殺傷活性,而它們針對表達低水準黏蛋白1的正常乳腺細胞系(MCF10A)沒有顯示出細胞毒性或細胞毒性顯著降低。
實例 7. 使用動物模型分析 CAR-T 細胞的抗癌療效 7-1. 使用胰腺癌動物模型對抗癌療效進行分析
給7周齡的NOG雌性小鼠皮下(subcutaneously,s.c.))注射6×10
6個PANC1-v1細胞(表達MUC1的PANC1胰腺癌細胞)。當腫瘤體積達到500立方毫米時,靜脈內(intravenously,i.v.)注射1×10
6個抗MUC1 CAR-T細胞(根據本揭露的表達含scFv的CAR的來源於供體18-09的T細胞),且然後觀察腫瘤生長。在CAR-T細胞注射後14天及28天收集血液,並觀察血液中的人免疫細胞(hCD45+細胞)的數目(每組n=5)。作為陰性對照,使用PBS(載具)注射組及不表達CAR的T細胞(對照T細胞)。
結果,如圖15及圖16中所示,觀察到500立方毫米大小的腫瘤變小,且在T細胞注射後約20天,在外觀上沒有觀察到腫瘤。相反,在陰性對照組中,腫瘤大小繼續增加。
接下來,在相同的動物模型中,當腫瘤體積超過1500立方毫米時(即,在PANC1-v1細胞注射後66天),靜脈內(i.v.)注射1×10
6或0.5×10
6個抗MUC1 CAR-T細胞,且然後觀察腫瘤生長(每組n=2)。
結果,如圖17中所示,腫瘤大小在早期增大。然而,在約10天后,大小逐漸減小,且在30天后,腫瘤大小變得太小而無法量測。
7-2. 使用乳腺癌動物模型對抗癌療效進行分析
給9周齡的NOG雌性小鼠皮下(s.c.)注射4×10
6個HCC1954細胞(天然表達MUC1的乳腺癌細胞系)。當腫瘤體積達到500立方毫米(細胞注射後23天)時,靜脈內(i.v.)注射0.5×10
6或0.1×10
6個抗MUC1 CAR-T細胞(根據本揭露的表達含scFv CAR的來源於供體20-01的T細胞),且然後觀察腫瘤生長(每組n=7)。在注射T細胞後,定期採集血液,並觀察血液中人免疫細胞(hCD45+細胞)的數目(每組n=3)。作為陰性對照,使用PBS(載具)注射組及不表達CAR的T細胞(對照T細胞)。
結果,如圖18及圖19中所示,在CAR-T細胞注射後,500立方毫米大小的腫瘤保持停滯7天。此後,大小迅速減小,且在25天后變得太小而無法量測。另外,小鼠血液中hCD45+細胞的數目有增加的趨勢,且在約25天后數目逐漸減少。似乎CAR-T細胞在識別抗原後被激活並增殖,且因此血液中的細胞數目增加。
基於以上說明,熟習此項技術者將理解,在不改變本揭露的技術精神或基本特徵的情况下,本揭露可以不同的具體形式實施。在此方面,應理解,上述實施例不是限制性的而是在所有態樣中均為例示性的。本揭露的範圍由所附申請專利範圍而不是由其之前的說明來限定,且因此落入申請專利範圍的邊界及界限內的所有改變及修改或者此種邊界及界限的等同物因此旨在包含在申請專利範圍內。
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圖1顯示根據本揭露一示例性實施例、對用於評估嵌合抗原受體(Chimeric Antigen Receptor,CAR)T細胞針對MUC1陽性腫瘤細胞(T47D,HEK293T-V1)的反應的細胞因子分泌進行分析的結果,所述CAR-T細胞使用來源於供體03及供體04的T細胞來製備。
圖2顯示根據本揭露一示例性實施例、對用於評估CAR-T細胞針對MUC1陽性腫瘤細胞(T47D)的反應的細胞因子分泌進行分析的結果,所述CAR-T細胞使用來源於供體06的T細胞來製備。
圖3顯示根據本揭露一示例性實施例、對用於評估CAR-T細胞針對不對黏蛋白1進行表達的細胞(HEK293T)的反應的細胞因子分泌進行分析的結果,所述CAR-T細胞使用來源於供體06的T細胞來製備。
圖4顯示對根據本揭露一示例性實施例、CAR-T細胞針對人乳腺癌細胞系T47D的細胞毒性進行測試的結果,所述CAR-T細胞使用來源於供體03的T細胞來製備。
圖5顯示對CAR-T細胞針對人乳腺癌細胞系T47D的細胞毒性進行測試的結果,所述CAR-T細胞使用來源於供體04的T細胞來製備。
圖6顯示對CAR-T細胞針對人胚胎腎細胞HEK293T的細胞毒性進行測試的結果,所述CAR-T細胞使用來源於供體03的T細胞來製備。
圖7顯示對CAR-T細胞針對人胚胎腎細胞HEK293T的細胞毒性進行測試的結果,所述CAR-T細胞使用來源於供體04的T細胞來製備。
圖8顯示對CAR-T細胞針對藉由在人胚胎腎細胞系中對外源MUC1-C進行表達所獲得的HEK293T-V1的細胞毒性進行測試的結果,所述CAR-T細胞使用來源於供體04的T細胞來製備。
圖9顯示對根據本揭露一示例性實施例的CAR-T細胞針對人乳腺癌細胞系T47D的細胞毒性進行測試的結果,所述CAR-T細胞使用來源於供體05的T細胞來製備。
圖10顯示對根據本揭露一示例性實施例的CAR-T細胞針對人乳腺癌細胞系T47D的細胞毒性進行測試的結果,所述CAR-T細胞使用來源於供體06的T細胞來製備。
圖11顯示對根據本揭露一示例性實施例的CAR-T細胞針對人胚胎腎細胞系HEK293T的細胞毒性進行測試的結果,所述CAR-T細胞使用來源於供體07的T細胞來製備。
圖12顯示對根據本揭露一示例性實施例的CAR-T細胞針對人乳腺癌細胞系HCC70(#2: 2447_2H08;#3: 2447_3A01;#4: 2447_3A08;#5: 2447_3A09;#6: 2447_3A12;#7: 2447_3B07;#8: 2447_3C08;#9: 2447_3H02;#10: 2447_3H08)的細胞毒性進行測試的結果,所述CAR-T細胞使用來源於供體08的T細胞來製備。
圖13顯示在效應細胞(E):靶細胞(T)的比率為0.3:1(#2: 2447_2H08)下、根據本揭露一示例性實施例的CAR-T細胞針對人乳腺癌細胞系(HCC70)及正常人乳腺細胞系(MCF10A)的不同細胞毒性的結果。
圖14顯示在效應細胞(E):靶細胞(T)的比率為0.1:1(#2: 2447_2H08)下、根據本揭露一示例性實施例的CAR-T細胞針對人乳腺癌細胞系(HCC70)及正常人乳腺細胞系(MCF10A)的不同細胞毒性的結果。
圖15顯示在將根據本揭露一示例性實施例的CAR-T細胞注射至已經注射有PANC1-v1細胞(表達MUC1的PANC1胰腺癌細胞)的癌症動物模型中之後對腫瘤生長抑制進行檢查的結果。
圖16顯示在將根據本揭露一示例性實施例的CAR-T細胞注射至已經注射有PANC1-v1細胞(表達MUC1的PANC1胰腺癌細胞)的癌症動物模型中之後14天及28天,對血液中的人免疫細胞(hCD45+細胞)的數目進行檢查的結果。
圖17顯示在將根據本揭露一示例性實施例的兩種不同劑量的CAR-T細胞注射至已經注射有PANC1-v1細胞(表達MUC1的PANC1胰腺癌細胞)的癌症動物模型中之後對腫瘤生長抑制進行檢查的結果。
圖18顯示在將根據本揭露一示例性實施例的CAR-T細胞注射至已經注射有HCC1954細胞(天然表達MUC1的乳腺癌細胞)的癌症動物模型中之後對腫瘤生長抑制進行檢查的結果。
圖19顯示在將根據本揭露一示例性實施例的CAR-T細胞注射至已經注射有HCC1954細胞(天然表達MUC1的乳腺癌細胞)的癌症動物模型中之後,以規則的時間間隔對血液中的人免疫細胞(hCD45+細胞)的數目進行檢查的結果。
<![CDATA[<110> LG 化學股份有限公司]]> <![CDATA[<120> 特定於黏蛋白1之多肽以及其應用]]> <![CDATA[<130> OPP20215468KR]]> <![CDATA[<150> KR10-2020-0183768]]> <![CDATA[<151> 2020-12-24]]> <![CDATA[<150> KR10-2021-0137757]]> <![CDATA[<151> 2021-10-15]]> <![CDATA[<160> 115]]> <![CDATA[<170> koPatentIn 3.0]]> <![CDATA[<210> 1]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2445_1F09 HCDR1]]> <![CDATA[<400> 1]]> Gly Phe Thr Val Ser Ser Asn Tyr 1 5 <![CDATA[<210> 2]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2445_1F09 HCDR2]]> <![CDATA[<400> 2]]> Ile Tyr Ser Gly Gly Ser Thr 1 5 <![CDATA[<210> 3]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2445_1F09 HCDR3]]> <![CDATA[<400> 3]]> Asp Arg Gly Trp Asn His Gly Met Asp Val 1 5 10 <![CDATA[<210> 4]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2445_1F09 LCDR1]]> <![CDATA[<400> 4]]> Ser Ser Glu Val Gly Ser Arg Tyr 1 5 <![CDATA[<210> 5]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2445_1F09 LCDR2]]> <![CDATA[<400> 5]]> Lys Asn Asp 1 <![CDATA[<210> 6]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2445_1F09 LCDR3]]> <![CDATA[<400> 6]]> Ala Ala Trp Asp Asp Ser Leu Asn Gly Tyr Val 1 5 10 <![CDATA[<210> 7]]> <![CDATA[<211> 118]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2445_1F09 VH]]> <![CDATA[<400> 7]]> Glu Val Gln Leu Leu Glu Thr Gly Gly Gly Leu Ile Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Asp Arg Gly Trp Asn His Gly Met Asp Val Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 8]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2445_1F09 VL]]> <![CDATA[<400> 8]]> Gln Ser Gly Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Gly Ser Ser Glu Val Gly Ser Arg 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Lys Asn Asp Arg Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Ser Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Asn Gly Tyr Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 9]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2445_1F09 scFv]]> <![CDATA[<400> 9]]> Glu Val Gln Leu Leu Glu Thr Gly Gly Gly Leu Ile Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Asp Arg Gly Trp Asn His Gly Met Asp Val Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Ala Ser Gln Ser Gly Leu Thr Gln Pro Pro Ser Ala Ser 130 135 140 Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Gly Ser Ser 145 150 155 160 Glu Val Gly Ser Arg Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr 165 170 175 Ala Pro Arg Leu Leu Ile Tyr Lys Asn Asp Arg Arg Pro Ser Gly Val 180 185 190 Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Ser Ser Ala Ser Leu Ala 195 200 205 Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala 210 215 220 Trp Asp Asp Ser Leu Asn Gly Tyr Val Phe Gly Thr Gly Thr Lys Leu 225 230 235 240 Thr Val Leu <![CDATA[<210> 10]]> <![CDATA[<211> 729]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2445_1F09 scFv]]> <![CDATA[<400> 10]]> gaggtgcagc tgttggagac tggaggaggc ttgatccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atattacgca 180 gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240 caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatcgcggc 300 tggaaccacg gtatggacgt ctggggccag ggaaccctgg tcaccgtctc gagtggtgga 360 ggcggttcag gcggaggtgg ctctggcggt ggcgctagcc agtctgggct gactcagcca 420 ccctcagcgt ctgggacccc cgggcagagg gtcaccatct cttgttctgg gggcagctca 480 gaagtcggaa gtagatatgt gtcctggtac cagcaactcc caggaacggc ccccagactc 540 ctcatctata agaatgatcg gcggccctca ggggtccctg accgattctc tggctccaag 600 tctggctcct cagcctccct ggccatcagt gggctccggt ccgaggatga ggctgattat 660 tactgtgcag catgggatga cagcctgaat ggttatgtct tcggaactgg gaccaagctg 720 accgtccta 729 <![CDATA[<210> 11]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_2H08 HCDR1]]> <![CDATA[<400> 11]]> Gly Tyr Thr Phe Thr Asn Tyr Gly 1 5 <![CDATA[<210> 12]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_2H08 HCDR2]]> <![CDATA[<400> 12]]> Ile Ser Ala Tyr Asn Gly Asn Thr 1 5 <![CDATA[<210> 13]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_2H08 HCDR3]]> <![CDATA[<400> 13]]> Asp Pro His Ile Leu Thr Gly Tyr Tyr Arg Gly Gly Trp Phe Asp Pro 1 5 10 15 <![CDATA[<210> 14]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_2H08 LCDR1]]> <![CDATA[<400> 14]]> Ser Leu Arg Thr Ser Tyr 1 5 <![CDATA[<210> 15]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_2H08 LCDR2]]> <![CDATA[<400> 15]]> Gly Lys Thr 1 <![CDATA[<210> 16]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_2H08 LCDR3]]> <![CDATA[<400> 16]]> His Ser Arg Asp Ser Asn Asp Asn Tyr Leu Glu Val Val 1 5 10 <![CDATA[<210> 17]]> <![CDATA[<211> 125]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_2H08 VH]]> <![CDATA[<400> 17]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Pro His Ile Leu Thr Gly Tyr Tyr Arg Gly Gly Trp Phe 100 105 110 Asp Pro Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 18]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_2H08 VL]]> <![CDATA[<400> 18]]> Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Val Thr Ile Thr Cys Gln Gly Asp Ser Leu Arg Thr Ser Tyr Ala 20 25 30 Gly Trp Leu Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Leu Tyr 35 40 45 Gly Lys Thr Ser Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Thr Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65 70 75 80 Asp Glu Ala Glu Tyr Phe Cys His Ser Arg Asp Ser Asn Asp Asn Tyr 85 90 95 Leu Glu Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 19]]> <![CDATA[<211> 250]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_2H08 scFv]]> <![CDATA[<400> 19]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Pro His Ile Leu Thr Gly Tyr Tyr Arg Gly Gly Trp Phe 100 105 110 Asp Pro Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ala Ser Ser Tyr Glu Leu 130 135 140 Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Thr Ile 145 150 155 160 Thr Cys Gln Gly Asp Ser Leu Arg Thr Ser Tyr Ala Gly Trp Leu Gln 165 170 175 Gln Lys Pro Gly Gln Ala Pro Val Leu Val Leu Tyr Gly Lys Thr Ser 180 185 190 Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Thr Ser Gly Asn 195 200 205 Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Glu 210 215 220 Tyr Phe Cys His Ser Arg Asp Ser Asn Asp Asn Tyr Leu Glu Val Val 225 230 235 240 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 245 250 <![CDATA[<210> 20]]> <![CDATA[<211> 750]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_2H08 scFv]]> <![CDATA[<400> 20]]> gaagtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg cttctggtta cacctttacc aactacggta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcagcgctt acaatggtaa cacaaactat 180 gcacagaagc tccagggcag agtcaccatg accacagaca catccacgag cacagcctac 240 atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gagagatccg 300 catattttga ctggttatta taggggaggg tggttcgacc cctgggggca agggaccacg 360 gtcaccgtct cgagtggtgg aggcggttca ggcggaggtg gctctggcgg tggcgctagc 420 tcctatgagc tgactcagga ccctgctgtg tctgtggcct tgggtcagac agtcaccatc 480 acgtgccaag gagacagcct cagaacctct tatgcaggct ggctccagca gaagccagga 540 caggcccctg tactcgtcct ctatggtaaa accagccggc cctcagggat cccagaccga 600 ttctctggct ccacctcagg aaacacagct tccttgacca tcactggggc tcaggcggag 660 gatgaggctg agtatttctg tcactcccgg gacagcaatg ataactatct agaggtggtt 720 ttcggcggag ggaccaagct gaccgtccta 750 <![CDATA[<210> 21]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A01 HCDR1]]> <![CDATA[<400> 21]]> Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <![CDATA[<210> 22]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A01 HCDR2]]> <![CDATA[<400> 22]]> Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <![CDATA[<210> 23]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A01 HCDR3]]> <![CDATA[<400> 23]]> Asp Ile Ser Ser Gly Trp Tyr Pro Gly Thr Phe Asp Tyr 1 5 10 <![CDATA[<210> 24]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A01 LCDR1]]> <![CDATA[<400> 24]]> Ser Leu Arg Ser Tyr Tyr 1 5 <![CDATA[<210> 25]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A01 LCDR2]]> <![CDATA[<400> 25]]> Gly Lys Asn 1 <![CDATA[<210> 26]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A01 LCDR3]]> <![CDATA[<400> 26]]> Ser Ser Arg Asp Ser Ser Asp Asp Val Val 1 5 10 <![CDATA[<210> 27]]> <![CDATA[<211> 122]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A01 VH]]> <![CDATA[<400> 27]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Val Tyr Ala Asp Phe Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Ser Ser Gly Trp Tyr Pro Gly Thr Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 28]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A01 VL]]> <![CDATA[<400> 28]]> Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala 20 25 30 Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Ser Ser Gly Asn Thr Ala Ser Leu Thr Val Thr Gly Ala Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Arg Asp Ser Ser Asp Asp Val 85 90 95 Val Phe Gly Gly Gly Thr Gln Leu Thr Val Leu 100 105 <![CDATA[<210> 29]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A01 scFv]]> <![CDATA[<400> 29]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Val Tyr Ala Asp Phe Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Ser Ser Gly Trp Tyr Pro Gly Thr Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Ala Ser Ser Tyr Glu Leu Thr Gln Asp 130 135 140 Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys Gln 145 150 155 160 Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro Ser 180 185 190 Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser 195 200 205 Leu Thr Val Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys 210 215 220 Ser Ser Arg Asp Ser Ser Asp Asp Val Val Phe Gly Gly Gly Thr Gln 225 230 235 240 Leu Thr Val Leu <![CDATA[<210> 30]]> <![CDATA[<211> 732]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A01 scFv]]> <![CDATA[<400> 30]]> gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag catagtctat 180 gcggactttg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagatatt 300 tcaagtggct ggtacccagg gacctttgac tactggggcc agggaaccct ggtcaccgtc 360 tcgagtggtg gaggcggttc aggcggaggt ggctctggcg gtggcgctag ctcctatgag 420 ctgactcagg accctgctgt gtctgtggcc ttgggacaga cagtcaggat cacatgccaa 480 ggagacagcc tcagaagcta ttatgcaagc tggtaccagc agaagccagg acaggcccct 540 gtacttgtca tctatggtaa aaacaaccgg ccctcaggga tcccagaccg attctctggc 600 tccagctcag gaaacacagc ttccttgacc gtcactgggg ctcaggcgga agacgaggct 660 gactattact gtagctcccg ggacagcagt gatgatgtgg tattcggcgg agggacccag 720 ctcaccgtcc ta 732 <![CDATA[<210> 31]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A08 HCDR1]]> <![CDATA[<400> 31]]> Gly Tyr Thr Phe Thr Ser Tyr Gly 1 5 <![CDATA[<210> 32]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A08 HCDR2]]> <![CDATA[<400> 32]]> Ile Ser Ala Tyr Asn Gly Asn Thr 1 5 <![CDATA[<210> 33]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A08 HCDR3]]> <![CDATA[<400> 33]]> Asp Arg Ala Thr Ile Phe Gly Val Val Thr Pro Phe Asp Tyr 1 5 10 <![CDATA[<210> 34]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A08 LCDR1]]> <![CDATA[<400> 34]]> Ser Ile Arg Ser Tyr Ser 1 5 <![CDATA[<210> 35]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A08 LCDR2]]> <![CDATA[<400> 35]]> Gly Lys Asn 1 <![CDATA[<210> 36]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A08 LCDR3]]> <![CDATA[<400> 36]]> Asn Ser Arg Asp Ser Ser Gly Asn Arg Val Val 1 5 10 <![CDATA[<210> 37]]> <![CDATA[<211> 123]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A08 VH]]> <![CDATA[<400> 37]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Ala Thr Ile Phe Gly Val Val Thr Pro Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 38]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A08 VL]]> <![CDATA[<400> 38]]> Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Ile Arg Ser Tyr Ser Ala 20 25 30 Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Val Ile Tyr 35 40 45 Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Val Ser Gly Ser 50 55 60 Thr Ser Gly Asn Thr Ala Ser Leu Thr Val Thr Gly Ala Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn Arg 85 90 95 Val Val Phe Gly Gly Gly Thr Gln Leu Thr Val Leu 100 105 <![CDATA[<210> 39]]> <![CDATA[<211> 246]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A08 scFv]]> <![CDATA[<400> 39]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Ala Thr Ile Phe Gly Val Val Thr Pro Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Gly Ala Ser Ser Tyr Glu Leu Thr Gln 130 135 140 Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys 145 150 155 160 Gln Gly Asp Ser Ile Arg Ser Tyr Ser Ala Ser Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Gln Ala Pro Arg Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro 180 185 190 Ser Gly Ile Pro Asp Arg Val Ser Gly Ser Thr Ser Gly Asn Thr Ala 195 200 205 Ser Leu Thr Val Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr 210 215 220 Cys Asn Ser Arg Asp Ser Ser Gly Asn Arg Val Val Phe Gly Gly Gly 225 230 235 240 Thr Gln Leu Thr Val Leu 245 <![CDATA[<210> 40]]> <![CDATA[<211> 738]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A08 scFv]]> <![CDATA[<400> 40]]> gaagtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg cttctggtta cacctttacc agctacggta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcagcgctt acaatggtaa cacaaactat 180 gcacagaagc tccagggcag agtcaccatg accacagaca catccacgag cacagcctac 240 atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gagagatcgg 300 gctacgattt ttggagtggt tacccccttt gactactggg gccaaggaac cctggtcacc 360 gtctcgagtg gtggaggcgg ttcaggcgga ggtggctctg gcggtggcgc tagctcctat 420 gagctgactc aggaccccgc tgtgtctgtg gccttgggac agacagtcag gatcacatgc 480 cagggagaca gtattagaag ttattctgcc agctggtacc agcagaagcc agggcaggcc 540 cctcgccttg ttatctatgg taaaaacaac cggccctcag ggatcccaga ccgagtctct 600 ggctccactt caggaaatac agcttccttg accgtcactg gggctcaggc ggaagatgag 660 gctgactatt actgtaactc ccgggacagc agtggtaacc gtgtggtatt cggcggaggg 720 acccagctca ccgtccta 738 <![CDATA[<210> 41]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A09 HCDR1]]> <![CDATA[<400> 41]]> Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <![CDATA[<210> 42]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A09 HCDR2]]> <![CDATA[<400> 42]]> Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <![CDATA[<210> 43]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A09 HCDR3]]> <![CDATA[<400> 43]]> Asp Val Ser Ser Gly Trp Tyr Trp Tyr Ala Phe Asp Ile 1 5 10 <![CDATA[<210> 44]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A09 LCDR1]]> <![CDATA[<400> 44]]> Ser Leu Arg Ser Tyr Tyr 1 5 <![CDATA[<210> 45]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A09 LCDR2]]> <![CDATA[<400> 45]]> Gly Lys Asn 1 <![CDATA[<210> 46]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A09 LCDR3]]> <![CDATA[<400> 46]]> Asn Ser Arg Asp Ser Gly Gly Ser Val Val 1 5 10 <![CDATA[<210> 47]]> <![CDATA[<211> 122]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A09 VH]]> <![CDATA[<400> 47]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Thr Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ser Tyr Tyr Cys 85 90 95 Ala Lys Asp Val Ser Ser Gly Trp Tyr Trp Tyr Ala Phe Asp Ile Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 48]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A09 VL]]> <![CDATA[<400> 48]]> Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala 20 25 30 Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Gly Arg Phe Ser Gly Ser 50 55 60 Ser Ser Gly Asn Thr Ala Ser Leu Thr Val Thr Gly Ala Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Gly Gly Ser Val 85 90 95 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <![CDATA[<210> 49]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A09 scFv]]> <![CDATA[<400> 49]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Thr Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ser Tyr Tyr Cys 85 90 95 Ala Lys Asp Val Ser Ser Gly Trp Tyr Trp Tyr Ala Phe Asp Ile Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Ala Ser Ser Tyr Glu Leu Thr Gln Asp 130 135 140 Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys Gln 145 150 155 160 Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro Ser 180 185 190 Gly Ile Pro Gly Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser 195 200 205 Leu Thr Val Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys 210 215 220 Asn Ser Arg Asp Ser Gly Gly Ser Val Val Phe Gly Gly Gly Thr Lys 225 230 235 240 Leu Thr Val Leu <![CDATA[<210> 50]]> <![CDATA[<211> 732]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A09 scFv]]> <![CDATA[<400> 50]]> gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag ccactggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggcctcgt attactgtgc aaaagatgtt 300 agcagtggct ggtactggta tgcttttgat atctggggcc aaggaaccct ggtcaccgtc 360 tcgagtggtg gaggcggttc aggcggaggt ggctctggcg gtggcgctag ctcctatgag 420 ctgactcagg accctgctgt gtctgtggcc ttgggacaga cagtcaggat cacatgccaa 480 ggagacagcc tcagaagcta ttatgcaagc tggtaccagc agaagccagg acaggcccct 540 gtacttgtca tctatggtaa aaacaaccgg ccctcaggga tcccaggccg attctctggc 600 tccagctcag gaaacacagc ttccttgacc gtcactgggg ctcaggcgga agatgaggct 660 gactattact gtaattcccg ggacagcggt ggttctgtgg ttttcggcgg agggaccaag 720 ctgaccgtcc ta 732 <![CDATA[<210> 51]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A12 HCDR1]]> <![CDATA[<400> 51]]> Gly Tyr Thr Phe Thr Ser Tyr Gly 1 5 <![CDATA[<210> 52]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A12 HCDR2]]> <![CDATA[<400> 52]]> Ile Ser Ala Tyr Asn Gly Asn Thr 1 5 <![CDATA[<210> 53]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A12 HCDR3]]> <![CDATA[<400> 53]]> Asp Pro His Ile Leu Thr Gly Tyr Tyr Arg Gly Gly Trp Phe Asp Pro 1 5 10 15 <![CDATA[<210> 54]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A12 LCDR1]]> <![CDATA[<400> 54]]> Ser Leu Arg Ser Tyr Tyr 1 5 <![CDATA[<210> 55]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A12 LCDR2]]> <![CDATA[<400> 55]]> Gly Lys Asn 1 <![CDATA[<210> 56]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A12 LCDR3]]> <![CDATA[<400> 56]]> Asn Ser Arg Asp Ser Ser Gly Asn His Arg Val 1 5 10 <![CDATA[<210> 57]]> <![CDATA[<211> 125]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A12 VH]]> <![CDATA[<400> 57]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Arg Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Pro His Ile Leu Thr Gly Tyr Tyr Arg Gly Gly Trp Phe 100 105 110 Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 58]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A12 VL]]> <![CDATA[<400> 58]]> Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Val Leu Gly Gln 1 5 10 15 Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala 20 25 30 Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His 85 90 95 Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <![CDATA[<210> 59]]> <![CDATA[<211> 248]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A12 scFv]]> <![CDATA[<400> 59]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Arg Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Pro His Ile Leu Thr Gly Tyr Tyr Arg Gly Gly Trp Phe 100 105 110 Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ala Ser Ser Tyr Glu Leu 130 135 140 Thr Gln Asp Pro Ala Val Ser Val Val Leu Gly Gln Thr Val Arg Ile 145 150 155 160 Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln 165 170 175 Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn 180 185 190 Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn 195 200 205 Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp 210 215 220 Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His Arg Val Phe Gly 225 230 235 240 Gly Gly Thr Lys Leu Thr Val Leu 245 <![CDATA[<210> 60]]> <![CDATA[<211> 744]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3A12 scFv]]> <![CDATA[<400> 60]]> gaagtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg cttctggtta cacctttacc agctatggta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcagcgctt acaatggtaa cacaaactat 180 gcacagaagc tccggggcag agtcaccatg accacagaca catccacgag cacagcctac 240 atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gagagatccg 300 catattttga ctggttatta taggggaggg tggttcgacc cctggggcca gggcaccctg 360 gtcaccgtct cgagtggtgg aggcggttca ggcggaggtg gctctggcgg tggcgctagc 420 tcctatgagc tgactcagga ccctgctgtg tctgtggtct tgggacagac agtcaggatc 480 acatgccaag gagacagcct cagaagctat tatgcaagct ggtaccagca gaagccagga 540 caggcccctg tacttgtcat ctatggtaaa aacaaccggc cctcagggat cccagaccga 600 ttctctggct ccagctcagg aaacacagct tccttgacca tcactggggc tcaggcggaa 660 gatgaggctg actattactg taactcccgg gacagcagtg gtaaccatcg tgtattcggc 720 ggagggacca agctgaccgt ccta 744 <![CDATA[<210> 61]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3B07 HCDR1]]> <![CDATA[<400> 61]]> Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <![CDATA[<210> 62]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3B07 HCDR2]]> <![CDATA[<400> 62]]> Thr Ser Trp Asp Gly Gly Ser Thr 1 5 <![CDATA[<210> 63]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3B07 HCDR3]]> <![CDATA[<400> 63]]> Asp His Ser Ser Gly Trp Tyr Asn Gly Gly 1 5 10 <![CDATA[<210> 64]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3B07 LCDR1]]> <![CDATA[<400> 64]]> Ser Leu Arg Ser Tyr Tyr 1 5 <![CDATA[<210> 65]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3B07 LCDR2]]> <![CDATA[<400> 65]]> Gly Lys Asn 1 <![CDATA[<210> 66]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3B07 LCDR3]]> <![CDATA[<400> 66]]> Asn Ser Arg Asp Ser Ser Gly Asn His Val Val 1 5 10 <![CDATA[<210> 67]]> <![CDATA[<211> 122]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3B07 VH]]> <![CDATA[<400> 67]]> Gln Val Gln Leu Val Glu Ser Gly Gly Val Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ser Leu Thr Ser Trp Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp His Ser Ser Gly Trp Tyr Asn Gly Gly Met Asp Val Trp 100 105 110 Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <![CDATA[<210> 68]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3B07 VL]]> <![CDATA[<400> 68]]> Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala 20 25 30 Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <![CDATA[<210> 69]]> <![CDATA[<211> 245]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3B07 scFv]]> <![CDATA[<400> 69]]> Gln Val Gln Leu Val Glu Ser Gly Gly Val Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ser Leu Thr Ser Trp Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp His Ser Ser Gly Trp Tyr Asn Gly Gly Met Asp Val Trp 100 105 110 Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Ala Ser Ser Tyr Glu Leu Thr Gln Asp 130 135 140 Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys Gln 145 150 155 160 Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro Ser 180 185 190 Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser 195 200 205 Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys 210 215 220 Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly Thr 225 230 235 240 Lys Leu Thr Val Leu 245 <![CDATA[<210> 70]]> <![CDATA[<211> 735]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3B07 scFv]]> <![CDATA[<400> 70]]> caggtgcagc tggtggagtc tgggggagtc gtggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccgtcaagct 120 ccggggaggg gtctggagtg ggtctctctt actagttggg atggtggtag cacatactat 180 gcagactctg tgaagggtcg attcaccatc tccagagaca acagcaaaaa ctccctgtat 240 ctgcaaatga acagtctgag agctgaggac accgccttgt attactgtgc aaaagatcat 300 agcagcggct ggtacaacgg gggtatggac gtctggggcc aagggacaat ggtcaccgtc 360 tcgagtggtg gaggcggttc aggcggaggt ggctctggcg gtggcgctag ctcctatgag 420 ctgactcagg accctgctgt gtctgtggcc ttgggacaga cagtcaggat cacatgccaa 480 ggagacagcc tcagaagcta ttatgcaagc tggtaccagc agaagccagg acaggcccct 540 gtacttgtca tctatggtaa aaacaaccgg ccctcaggga tcccagaccg attctctggc 600 tccagctcag gaaacacagc ttccttgacc atcactgggg ctcaggcgga agatgaggct 660 gactattact gtaactcccg ggacagcagt ggtaaccatg tggtattcgg cggagggacc 720 aagctgaccg tccta 735 <![CDATA[<210> 71]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3C08 HCDR1]]> <![CDATA[<400> 71]]> Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <![CDATA[<210> 72]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3C08 HCDR2]]> <![CDATA[<400> 72]]> Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <![CDATA[<210> 73]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3C08 HCDR3]]> <![CDATA[<400> 73]]> Asp Arg Gly Ser Gly Tyr Glu Gly Asn Tyr Tyr Gly Met Asp Val 1 5 10 15 <![CDATA[<210> 74]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3C08 LCDR1]]> <![CDATA[<400> 74]]> Ser Leu Arg Ser Tyr Tyr 1 5 <![CDATA[<210> 75]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3C08 LCDR2]]> <![CDATA[<400> 75]]> Gly Lys Asn 1 <![CDATA[<210> 76]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3C08 LCDR3]]> <![CDATA[<400> 76]]> Asn Ser Arg Asp Ser Ser Gly Asn His Tyr Val 1 5 10 <![CDATA[<210> 77]]> <![CDATA[<211> 124]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3C08 VH]]> <![CDATA[<400> 77]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Arg Gly Ser Gly Tyr Glu Gly Asn Tyr Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 78]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3C08 VL]]> <![CDATA[<400> 78]]> Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala 20 25 30 Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Thr 50 55 60 Thr Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His 85 90 95 Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu 100 105 <![CDATA[<210> 79]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3C08 scFv]]> <![CDATA[<400> 79]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Arg Gly Ser Gly Tyr Glu Gly Asn Tyr Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Ala Ser Ser Tyr Glu Leu Thr 130 135 140 Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr 145 150 155 160 Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln 165 170 175 Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg 180 185 190 Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Thr Thr Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His Tyr Val Phe Gly Thr 225 230 235 240 Gly Thr Lys Val Thr Val Leu 245 <![CDATA[<210> 80]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3C08 scFv]]> <![CDATA[<400> 80]]> gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagatagg 300 ggtagtggct acgaaggaaa ctactacggt atggacgtct ggggccaagg aaccctggtc 360 accgtctcga gtggtggagg cggttcaggc ggaggtggct ctggcggtgg cgctagctcc 420 tatgagctga ctcaggaccc tgctgtgtct gtggccttgg gacagacagt caggatcaca 480 tgccaaggag acagcctcag aagctattat gcaagctggt accagcagaa gccaggacag 540 gcccctgtac ttgtcatcta tggtaaaaac aaccggccct cagggatccc agaccgattc 600 tctggtacca cctcaggaaa cacagcctcc ttgaccatca ctggggctca ggcggaagat 660 gaggctgact attactgtaa ctcccgggac agcagtggta accattatgt cttcggaact 720 gggaccaagg tcaccgtcct a 741 <![CDATA[<210> 81]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H02 HCDR1]]> <![CDATA[<400> 81]]> Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <![CDATA[<210> 82]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H02 HCDR2]]> <![CDATA[<400> 82]]> Ile Ser Trp Asp Ser Gly Ser Ile 1 5 <![CDATA[<210> 83]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H02 HCDR3]]> <![CDATA[<400> 83]]> Asp Val Ser Ser Gly Trp Tyr Trp Tyr Ala Phe Asp Ile 1 5 10 <![CDATA[<210> 84]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H02 LCDR1]]> <![CDATA[<400> 84]]> Ile Leu Arg Ser Tyr Tyr 1 5 <![CDATA[<210> 85]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H02 LCDR2]]> <![CDATA[<400> 85]]> Gly Lys Asn 1 <![CDATA[<210> 86]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H02 LCDR3]]> <![CDATA[<400> 86]]> Asn Ser Arg Asp Ser Ser Gly Asn Arg Val Val 1 5 10 <![CDATA[<210> 87]]> <![CDATA[<211> 122]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H02 VH]]> <![CDATA[<400> 87]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asp Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Val Ser Ser Gly Trp Tyr Trp Tyr Ala Phe Asp Ile Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 88]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H02 VL]]> <![CDATA[<400> 88]]> Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Val Arg Ile Thr Cys Gln Gly Asp Ile Leu Arg Ser Tyr Tyr Ala 20 25 30 Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn Arg 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <![CDATA[<210> 89]]> <![CDATA[<211> 245]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H02 scFv]]> <![CDATA[<400> 89]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asp Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Val Ser Ser Gly Trp Tyr Trp Tyr Ala Phe Asp Ile Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Ala Ser Ser Tyr Glu Leu Thr Gln Asp 130 135 140 Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys Gln 145 150 155 160 Gly Asp Ile Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro Ser 180 185 190 Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser 195 200 205 Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys 210 215 220 Asn Ser Arg Asp Ser Ser Gly Asn Arg Val Val Phe Gly Gly Gly Thr 225 230 235 240 Lys Leu Thr Val Leu 245 <![CDATA[<210> 90]]> <![CDATA[<211> 735]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H02 scFv]]> <![CDATA[<400> 90]]> gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttggg atagtggtag cataggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagatgtt 300 agcagtggct ggtactggta tgcttttgat atctggggcc agggaaccct ggtcaccgtc 360 tcgagtggtg gaggcggttc aggcggaggt ggctctggcg gtggcgctag ctcctatgag 420 ctgactcagg accctgctgt gtctgtggcc ttgggacaga cagtcaggat cacatgccaa 480 ggagacatcc tcagaagtta ttatgcaagt tggtaccagc agaagccagg acaggcccct 540 gtacttgtca tttatggtaa aaacaaccgg ccctcaggga tcccagaccg attctctggc 600 tccagctcag gaaacacagc ttccttgacc atcactgggg ctcaggcgga agatgaggct 660 gactattact gtaactcccg ggacagcagt ggtaaccgtg tggtattcgg cggagggacc 720 aagctgaccg tccta 735 <![CDATA[<210> 91]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H08 HCDR1]]> <![CDATA[<400> 91]]> Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <![CDATA[<210> 92]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H08 HCDR2]]> <![CDATA[<400> 92]]> Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <![CDATA[<210> 93]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H08 HCDR3]]> <![CDATA[<400> 93]]> Asp Arg Ser Ser Gly Trp Tyr Thr Gly Ser Phe Asp Tyr 1 5 10 <![CDATA[<210> 94]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H08 LCDR1]]> <![CDATA[<400> 94]]> Ser Leu Arg Ser Tyr Tyr 1 5 <![CDATA[<210> 95]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H08 LCDR2]]> <![CDATA[<400> 95]]> Gly Lys Asn 1 <![CDATA[<210> 96]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H08 LCDR3]]> <![CDATA[<400> 96]]> Gln Ser Arg Asp Ser Ser Asp Asn Arg Val Leu 1 5 10 <![CDATA[<210> 97]]> <![CDATA[<211> 122]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H08 VH]]> <![CDATA[<400> 97]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Ser Ser Gly Trp Tyr Thr Gly Ser Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 98]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H08 VL]]> <![CDATA[<400> 98]]> Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala 20 25 30 Ser Trp Tyr Arg Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Ile Gly Ala Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Arg Asp Ser Ser Asp Asn Arg 85 90 95 Val Leu Phe Gly Gly Gly Thr Lys Val Thr Val Leu 100 105 <![CDATA[<210> 99]]> <![CDATA[<211> 245]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H08 scFv]]> <![CDATA[<400> 99]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Ser Ser Gly Trp Tyr Thr Gly Ser Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Ala Ser Ser Tyr Glu Leu Thr Gln Asp 130 135 140 Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys Gln 145 150 155 160 Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Arg Gln Lys Pro 165 170 175 Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro Ser 180 185 190 Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser 195 200 205 Leu Thr Ile Ile Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys 210 215 220 Gln Ser Arg Asp Ser Ser Asp Asn Arg Val Leu Phe Gly Gly Gly Thr 225 230 235 240 Lys Val Thr Val Leu 245 <![CDATA[<210> 100]]> <![CDATA[<211> 735]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 2447_3H08 scFv]]> <![CDATA[<400> 100]]> gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag catagactat 180 gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agctgaggac acagctgtgt actactgtgc gagagatcgg 300 agtagtggct ggtacacggg gtcctttgac tactggggcc agggcaccct ggtcaccgtc 360 tcgagtggtg gaggcggttc aggcggaggt ggctctggcg gtggcgctag ctcctatgag 420 ctgactcagg accctgctgt gtctgtggcc ttgggacaga cagtcaggat cacatgccaa 480 ggagacagcc tcagaagcta ttatgcaagc tggtaccggc agaagccagg acaggcccct 540 gtacttgtca tctatggtaa aaacaaccgg ccctcaggga tcccagaccg attctctggc 600 tccagctcgg gaaacacagc ttccttgacc atcattgggg ctcaggcgga agacgaggct 660 gactattact gtcagtcccg ggacagcagt gataaccgtg ttctattcgg cggagggacc 720 aaggtcaccg tccta 735 <![CDATA[<210> 101]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> G03 HCDR1]]> <![CDATA[<400> 101]]> Gly Tyr Thr Phe Thr Ser Tyr Trp 1 5 <![CDATA[<210> 102]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> G03 HCDR2]]> <![CDATA[<400> 102]]> Ile Asn Pro Gly Thr Gly Tyr Ile 1 5 <![CDATA[<210> 103]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> G03 HCDR3]]> <![CDATA[<400> 103]]> Ser Thr Ala Pro Phe Asp Tyr 1 5 <![CDATA[<210> 104]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> G03 LCDR1]]> <![CDATA[<400> 104]]> Gln Asp Ile Lys Ser Tyr 1 5 <![CDATA[<210> 105]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> G03 LCDR2]]> <![CDATA[<400> 105]]> Tyr Ala Thr 1 <![CDATA[<210> 106]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> G03 LCDR3]]> <![CDATA[<400> 106]]> Leu Gln Tyr Asp Glu Ser Pro Tyr Thr 1 5 <![CDATA[<210> 107]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> G03 VH]]> <![CDATA[<400> 107]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Gly Thr Gly Tyr Ile Glu Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Ser Thr Ala Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <![CDATA[<210> 108]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> G03 VL]]> <![CDATA[<400> 108]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Ile Lys Ser Tyr 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Tyr Ala Thr Arg Leu Ala Asp Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Tyr Asp Glu Ser Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <![CDATA[<210> 109]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> G03 scFv]]> <![CDATA[<400> 109]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Gly Thr Gly Tyr Ile Glu Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Ser Thr Ala Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Ala Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu 130 135 140 Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Ile 145 150 155 160 Lys Ser Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg 165 170 175 Leu Leu Ile Tyr Tyr Ala Thr Arg Leu Ala Asp Gly Ile Pro Asp Arg 180 185 190 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg 195 200 205 Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Tyr Asp Glu 210 215 220 Ser Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 225 230 235 <![CDATA[<210> 110]]> <![CDATA[<211> 113]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> mucin 1]]> <![CDATA[<400> 110]]> Ser Phe Phe Phe Leu Ser Phe His Ile Ser Asn Leu Gln Phe Asn Ser 1 5 10 15 Ser Leu Glu Asp Pro Ser Thr Asp Tyr Tyr Gln Glu Leu Gln Arg Asp 20 25 30 Ile Ser Glu Met Phe Leu Gln Ile Tyr Lys Gln Gly Gly Phe Leu Gly 35 40 45 Leu Ser Asn Ile Lys Phe Arg Pro Gly Ser Val Val Val Gln Leu Thr 50 55 60 Leu Ala Phe Arg Glu Gly Thr Ile Asn Val His Asp Val Glu Thr Gln 65 70 75 80 Phe Asn Gln Tyr Lys Thr Glu Ala Ala Ser Arg Tyr Asn Leu Thr Ile 85 90 95 Ser Asp Val Ser Val Ser Asp Val Pro Phe Pro Phe Ser Ala Gln Ser 100 105 110 Gly <![CDATA[<210> 111]]> <![CDATA[<211> 182]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CD4]]> <![CDATA[<400> 111]]> Thr Ser Ile Thr Ala Tyr Lys Ser Glu Gly Glu Ser Ala Glu Phe Ser 1 5 10 15 Phe Pro Leu Asn Leu Gly Glu Glu Ser Leu Gln Gly Glu Leu Arg Trp 20 25 30 Lys Ala Glu Lys Ala Pro Ser Ser Gln Ser Trp Ile Thr Phe Ser Leu 35 40 45 Lys Asn Gln Lys Val Ser Val Gln Lys Ser Thr Ser Asn Pro Lys Phe 50 55 60 Gln Leu Ser Glu Thr Leu Pro Leu Thr Leu Gln Ile Pro Gln Val Ser 65 70 75 80 Leu Gln Phe Ala Gly Ser Gly Asn Leu Thr Leu Thr Leu Asp Arg Gly 85 90 95 Ile Leu Tyr Gln Glu Val Asn Leu Val Val Met Lys Val Thr Gln Pro 100 105 110 Asp Ser Asn Thr Leu Thr Cys Glu Val Met Gly Pro Thr Ser Pro Lys 115 120 125 Met Arg Leu Ile Leu Lys Gln Glu Asn Gln Glu Ala Arg Val Ser Arg 130 135 140 Gln Glu Lys Val Ile Gln Val Gln Ala Pro Glu Ala Gly Val Trp Gln 145 150 155 160 Cys Leu Leu Ser Glu Gly Glu Glu Val Lys Met Asp Ser Lys Ile Gln 165 170 175 Val Leu Ser Lys Gly Leu 180 <![CDATA[<210> 112]]> <![CDATA[<211> 135]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 鉸鏈域]]> <![CDATA[<400> 112]]> accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60 tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120 gacttcgcct gtgat 135 <![CDATA[<210> 113]]> <![CDATA[<211> 81]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> CD28跨膜域]]> <![CDATA[<400> 113]]> ttttgggtgc tggtggtggt tggtggagtc ctggcttgct atagcttgct agtaacagtg 60 gcctttatta ttttctgggt g 81 <![CDATA[<210> 114]]> <![CDATA[<211> 123]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> CD28共刺激域]]> <![CDATA[<400> 114]]> aggagtaaga ggagcaggct cctgcacagt gactacatga acatgactcc ccgccgcccc 60 gggcccaccc gcaagcatta ccagccctat gccccaccac gcgacttcgc agcctatcgc 120 tcc 123 <![CDATA[<210> 115]]> <![CDATA[<211> 336]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> CD3ζ細胞內傳訊域]]> <![CDATA[<400> 115]]> agagtgaagt tcagcaggag cgcagacgcc cccgcgtacc agcagggcca gaaccagctc 60 tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc 120 cgggaccctg agatgggggg aaagccgaga aggaagaacc ctcaggaagg cctgtacaat 180 gaactgcaga aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc 240 cggaggggca aggggcacga tggcctttac cagggtctca gtacagccac caaggacacc 300 tacgacgccc ttcacatgca ggccctgccc cctcgc 336
Claims (25)
- 一種與黏蛋白1結合的多肽,所述多肽包括選自以下重鏈可變(VH)區及輕鏈可變(VL)區的一對重鏈可變區及輕鏈可變區: -包含分別由胺基酸序列SEQ ID NO: 1、SEQ ID NO: 2及SEQ ID NO: 3表示的互補決定區(CDR)1、互補決定區2及互補決定區3的重鏈可變區、及包含分別由胺基酸序列SEQ ID NO: 4、SEQ ID NO: 5及SEQ ID NO: 6表示的互補決定區1、互補決定區2及互補決定區3的輕鏈可變區; -包含分別由胺基酸序列SEQ ID NO: 11、SEQ ID NO: 12及SEQ ID NO: 13表示的互補決定區1、互補決定區2及互補決定區3的重鏈可變區、及包含分別由胺基酸序列SEQ ID NO: 14、SEQ ID NO: 15及SEQ ID NO: 16表示的互補決定區1、互補決定區2及互補決定區3的輕鏈可變區; -包含分別由胺基酸序列SEQ ID NO: 21、SEQ ID NO: 22及SEQ ID NO: 23表示的互補決定區1、互補決定區2及互補決定區3的重鏈可變區、及包含分別由胺基酸序列SEQ ID NO: 24、SEQ ID NO: 25及SEQ ID NO: 26表示的互補決定區1、互補決定區2及互補決定區3的輕鏈可變區; -包含分別由胺基酸序列SEQ ID NO: 31、SEQ ID NO: 32及SEQ ID NO: 33表示的互補決定區1、互補決定區2及互補決定區3的重鏈可變區及包含分別由胺基酸序列SEQ ID NO: 44、SEQ ID NO: 45及SEQ ID NO: 46表示的互補決定區1、互補決定區2及互補決定區3的輕鏈可變區; -包含分別由胺基酸序列SEQ ID NO: 51、SEQ ID NO: 52及SEQ ID NO: 53表示的互補決定區1、互補決定區2及互補決定區3的重鏈可變區、及包含分別由胺基酸序列SEQ ID NO: 54、SEQ ID NO: 55及SEQ ID NO: 56表示的互補決定區1、互補決定區2及互補決定區3的輕鏈可變區; -包含分別由胺基酸序列SEQ ID NO: 61、SEQ ID NO: 62及SEQ ID NO: 63表示的互補決定區1、互補決定區2及互補決定區3的重鏈可變區、及包含分別由胺基酸序列SEQ ID NO: 64、SEQ ID NO: 65及SEQ ID NO: 66表示的互補決定區1、互補決定區2及互補決定區3的輕鏈可變區; -包含分別由胺基酸序列SEQ ID NO: 71、SEQ ID NO: 72及SEQ ID NO: 73表示的互補決定區1、互補決定區2及互補決定區3的重鏈可變區、及包含分別由胺基酸序列SEQ ID NO: 74、SEQ ID NO: 75及SEQ ID NO: 76表示的互補決定區1、互補決定區2及互補決定區3的輕鏈可變區; -包含分別由胺基酸序列SEQ ID NO: 81、SEQ ID NO: 82及SEQ ID NO: 83表示的互補決定區1、互補決定區2及互補決定區3的重鏈可變區、及包含分別由胺基酸序列SEQ ID NO: 84、SEQ ID NO: 85及SEQ ID NO: 86表示的互補決定區1、互補決定區2及互補決定區3的輕鏈可變區;以及 -包含分別由胺基酸序列SEQ ID NO: 91、SEQ ID NO: 92及SEQ ID NO: 93表示的互補決定區1、互補決定區2及互補決定區3的重鏈可變區、及包含分別由胺基酸序列SEQ ID NO: 94、SEQ ID NO: 95及SEQ ID NO: 96表示的互補決定區1、互補決定區2及互補決定區3的輕鏈可變區。
- 如請求項1所述的黏蛋白1結合多肽,包含選自以下重鏈可變(VH)區及輕鏈可變(VL)區的一對重鏈可變區及輕鏈可變區: -包含胺基酸序列SEQ ID NO: 7的重鏈可變區及包含胺基酸序列SEQ ID NO: 8的輕鏈可變區; -包含胺基酸序列SEQ ID NO: 17的重鏈可變區及包含胺基酸序列SEQ ID NO: 18的輕鏈可變區; -包含胺基酸序列SEQ ID NO: 27的重鏈可變區及包含胺基酸序列SEQ ID NO: 28的輕鏈可變區; -包含胺基酸序列SEQ ID NO: 37的重鏈可變區及包含胺基酸序列SEQ ID NO: 38的輕鏈可變區; -包含胺基酸序列SEQ ID NO: 47的重鏈可變區及包含胺基酸序列SEQ ID NO: 48的輕鏈可變區; -包含胺基酸序列SEQ ID NO: 57的重鏈可變區及包含胺基酸序列SEQ ID NO: 58的輕鏈可變區; -包含胺基酸序列SEQ ID NO: 67的重鏈可變區及包含胺基酸序列SEQ ID NO: 68的輕鏈可變區; -包含胺基酸序列SEQ ID NO: 77的重鏈可變區及包含胺基酸序列SEQ ID NO: 78的輕鏈可變區; -包含胺基酸序列SEQ ID NO: 87的重鏈可變區及包含胺基酸序列SEQ ID NO: 88的輕鏈可變區;以及 -包含胺基酸序列SEQ ID NO: 97的重鏈可變區及包含胺基酸序列SEQ ID NO: 98的輕鏈可變區。
- 如請求項1所述的黏蛋白1結合多肽,其中所述多肽為抗體或其抗原結合片段。
- 如請求項1所述的黏蛋白1結合多肽,其中所述多肽為單鏈可變片段(scFv)、肽抗體、片段抗原結合(Fab)、單株抗體、雙特異性抗體、微抗體、域抗體、合成抗體、嵌合抗體、人源化抗體、人抗體或抗體融合蛋白。
- 如請求項1所述的黏蛋白1結合多肽,其中所述重鏈可變區與所述輕鏈可變區藉由連接子彼此連接。
- 如請求項5所述的黏蛋白1結合多肽,其中所述連接子的胺基酸序列為GGGGSGGGGSGGGAS。
- 如請求項1所述的黏蛋白1結合多肽,其中單鏈可變片段包括選自由以下組成的群組的胺基酸序列:SEQ ID NO: 9、SEQ ID NO: 19、SEQ ID NO: 29、SEQ ID NO: 39、SEQ ID NO: 49、SEQ ID NO: 59、SEQ ID NO: 69、SEQ ID NO: 79、SEQ ID NO: 89及SEQ ID NO: 99。
- 一種分離的多核苷酸,對如請求項1至7中任一項所述的黏蛋白1結合多肽進行編碼。
- 一種載體,包含如請求項8所述的多核苷酸。
- 一種細胞,包含如請求項9所述的載體。
- 一種嵌合抗原受體,包括如請求項1至7中任一項所述的黏蛋白1結合多肽。
- 如請求項11所述的嵌合抗原受體,包括包含所述黏蛋白1結合多肽的細胞外域;跨膜域;以及細胞內傳訊域。
- 如請求項12所述的嵌合抗原受體,其中所述細胞外域更包括所述黏蛋白1結合多肽與所述跨膜域之間的間隔區。
- 如請求項13所述的嵌合抗原受體,其中所述間隔區包括CD8α或CD28的鉸鏈區、或者免疫球蛋白(IgG)的恆定區的全部或部分。
- 如請求項12所述的嵌合抗原受體,其中所述跨膜域為CD28或CD8的跨膜域。
- 如請求項12所述的嵌合抗原受體,其中所述細胞內傳訊域為CD3ζ傳訊域。
- 如請求項12所述的嵌合抗原受體,更包含一或多個共刺激域。
- 如請求項17所述的嵌合抗原受體,其中所述共刺激域位於所述跨膜域與所述細胞內傳訊域之間。
- 如請求項17所述的嵌合抗原受體,其中所述共刺激域為CD28、OX-40、4-1BB(CD137)、CD27或可誘導共刺激分子(ICOS)的傳訊域。
- 一種分離的多核苷酸,對如請求項11所述的嵌合抗原受體進行編碼。
- 一種載體,包含如請求項20所述的多核苷酸。
- 一種免疫細胞,對嵌合抗原受體進行表達,所述免疫細胞包含如請求項1至7中任一項所述的黏蛋白1結合多肽、或者包含對所述嵌合抗原受體進行編碼的多核苷酸。
- 如請求項22所述的免疫細胞,其中所述免疫細胞為T細胞、腫瘤浸潤淋巴細胞(TIL)、自然殺手(NK)細胞、T細胞受體表達細胞、樹突狀細胞或自然殺手T細胞。
- 如請求項22所述的免疫細胞,其中所述免疫細胞為自體T細胞或同種異體T細胞。
- 一種組成物,用於預防或治療癌症,所述組成物包含: 如請求項1至7中任一項所述的黏蛋白1結合多肽; 對所述黏蛋白1結合多肽進行編碼的分離的多核苷酸; 包含對所述黏蛋白1結合多肽進行編碼的所述多核苷酸的載體; 細胞,包含對所述黏蛋白1結合多肽進行編碼的所述多核苷酸; 嵌合抗原受體,包含所述黏蛋白1結合多肽; 對所述嵌合抗原受體進行編碼的分離的多核苷酸,; 包含對所述嵌合抗原受體進行編碼的所述多核苷酸的載體;或者 免疫細胞,包含對所述嵌合抗原受體進行編碼的所述多核苷酸或者對所述嵌合抗原受體進行表達。
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